U.S. patent number 6,342,503 [Application Number 09/004,150] was granted by the patent office on 2002-01-29 for 1n-alkyl-n-arylpyrimidinamines and derivatives thereof.
This patent grant is currently assigned to DuPont Pharmaceuticals Company. Invention is credited to Paul Edward Aldrich, Argyrios Georgios Arvanitis, Robert Scott Cheeseman, Robert John Chorvat, Thomas Eugene Christos, Paul Joseph Gilligan, Dimitri Emil Grigoriadis, Carl Nicholas Hodge, Paul John Krenitsky, Everett Latham Scholfield, Sang William Tam, Zelda Rakowitz Wasserman.
United States Patent |
6,342,503 |
Aldrich , et al. |
January 29, 2002 |
1N-alkyl-n-arylpyrimidinamines and derivatives thereof
Abstract
The present invention provides novel compounds, compounds and
pharmaceutical compositions thereof, and methods of using same in
the treatment of affective disorders, anxiety, depression,
post-traumatic stress disorders, eating disorders, supranuclear
palsy, irritable bowel syndrome, immune suppression,
Alzheimer'disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, or fertility problems. The novel compounds provided by
this invention are those of formula: ##STR1## wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, Z, Y, V, X, X', J, K, L, and M are as
defined herein.
Inventors: |
Aldrich; Paul Edward
(Wilmington, DE), Arvanitis; Argyrios Georgios (Kennett
Square, PA), Cheeseman; Robert Scott (Phoenixville, PA),
Chorvat; Robert John (West Chester, PA), Christos; Thomas
Eugene (Oxford, PA), Gilligan; Paul Joseph (Wilmington,
DE), Grigoriadis; Dimitri Emil (Carlsbad, CA), Hodge;
Carl Nicholas (Wilmington, DE), Krenitsky; Paul John
(Newark, DE), Scholfield; Everett Latham (New Castle,
DE), Tam; Sang William (Boston, MA), Wasserman; Zelda
Rakowitz (Wilmington, DE) |
Assignee: |
DuPont Pharmaceuticals Company
(Wilmington, DE)
|
Family
ID: |
27384537 |
Appl.
No.: |
09/004,150 |
Filed: |
January 7, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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315660 |
Sep 29, 1994 |
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297274 |
Aug 26, 1994 |
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134209 |
Oct 12, 1993 |
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Current U.S.
Class: |
514/272; 514/275;
544/324; 544/331; 544/332; 544/330; 544/323 |
Current CPC
Class: |
A61K
31/44 (20130101); C07D 487/04 (20130101); A61K
31/53 (20130101); A61K 31/535 (20130101); C07D
213/74 (20130101); C07D 239/42 (20130101); C07D
239/48 (20130101); C07D 251/18 (20130101); C07D
401/04 (20130101); C07D 401/06 (20130101); C07D
401/12 (20130101); C07D 403/04 (20130101); C07D
403/06 (20130101); C07D 403/12 (20130101); C07D
405/12 (20130101); C07D 409/04 (20130101); C07D
409/12 (20130101); C07D 417/04 (20130101); C07D
417/12 (20130101); C07D 471/04 (20130101); C07D
473/34 (20130101); C07D 473/40 (20130101); A61K
31/505 (20130101) |
Current International
Class: |
A61K
31/535 (20060101); A61K 31/505 (20060101); C07D
409/04 (20060101); C07D 417/04 (20060101); C07D
403/00 (20060101); C07D 401/04 (20060101); C07D
471/00 (20060101); C07D 417/00 (20060101); C07D
401/06 (20060101); C07D 401/12 (20060101); C07D
401/00 (20060101); C07D 251/00 (20060101); C07D
473/40 (20060101); C07D 239/48 (20060101); C07D
239/42 (20060101); C07D 487/00 (20060101); C07D
487/04 (20060101); C07D 213/00 (20060101); A61K
31/44 (20060101); C07D 473/34 (20060101); C07D
417/12 (20060101); C07D 403/04 (20060101); C07D
471/04 (20060101); A61K 31/53 (20060101); C07D
403/12 (20060101); C07D 473/00 (20060101); C07D
405/00 (20060101); C07D 405/12 (20060101); C07D
403/06 (20060101); C07D 409/12 (20060101); C07D
409/00 (20060101); C07D 251/18 (20060101); C07D
239/00 (20060101); C07D 213/74 (20060101); C07D
239/42 (); C07D 239/48 (); A61K 031/505 () |
Field of
Search: |
;514/272,275
;544/323,324,330,331,332 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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EP |
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0588762 |
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WO 8901938 |
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WO |
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WO 9118887 |
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WO |
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WO |
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WO |
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WO 9413676 |
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Jun 1994 |
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WO |
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WO 9413677 |
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Jun 1994 |
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WO |
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Other References
Dunn and Berridge, Physiological and behavioral responses to
corticotropin-releasing factor administration: is CRF a mediator of
anxiety or stress responses?, Brain Research Reviews, 15, 71-100,
1990. .
R. Chambers et al., Polyhalogenoheterocyclic compounds Part 40.
Tertiary Aromatic Amines as Carbon Nucleophiles, Tetrahedron, 48,
7939-7950, 1992. .
R.C. Young Et Al, Purine Derivatives as Competitive Inhibitors of
Human Erythrocyte Membrane Phosphatidylinositol 4-Kinase, Journal
of Medicinal Chemistry, 33, 2073-2080, 1990..
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Rao; Deepak R.
Attorney, Agent or Firm: Black; Robert W. Rubin; Kenneth B.
Fuzail; Kalim S.
Parent Case Text
CROSS-REFERENCE TO EARLIER FILED APPLICATIONS
This is a continuation, of application Ser. No. 08/315,660 filed
Sep. 29, 1994 now abandoned which is a continuation-in-part of U.S.
patent application Ser. No. 08/297,274 filed, Aug. 26, 1994, now
abandoned, which is a continuation-in-part of U.S. patent
application Ser. No. 08/134,209, filed Oct. 12, 1993 now abandoned.
The disclosures of these earlier filed applications are hereby
incorporated herein by reference.
Claims
What is claimed is:
1. A compound of formula (I): ##STR71##
or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is independently selected, at each occurrence from the
group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4
alkenyl, C.sub.2 -C.sub.4 alkynyl, and C.sub.1 -C.sub.2
haloalkyl;
R.sup.3 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.1 -C.sub.2 haloalkyl, nitro, NR.sup.6 R.sup.7, OR.sup.8,
S(O).sub.n R.sup.8, C(.dbd.O)R.sup.9, C(.dbd.O)NR.sup.6 R.sup.7,
C(.dbd.S)NR.sup.6 R.sup.7, --(CHR.sup.16).sub.k NR.sup.6 R.sup.7,
(CH.sub.2).sub.k OR.sup.8, C(.dbd.O)NR.sup.10 CH(R.sup.11)CO.sub.2
R.sup.12, --C(OH)(R.sup.25)(R.sup.25a), --(CH.sub.2).sub.p
S(O).sub.n -alkyl, --(CHR.sup.16)R.sup.25,
--C(CN)(R.sup.25)(R.sup.16), --C(.dbd.O)R.sup.25, --CH(CO.sub.2
R.sup.16).sub.2, NR.sup.10 C(.dbd.O)CH(R.sup.11)NR.sup.10 R.sup.12,
NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12 ;
K and L are each independently CX';
R.sup.2 is independently selected at each occurrence from the group
consisting of hydrogen, halo, halomethyl, C.sub.1 -C.sub.3 alkyl,
and cyano;
R.sup.4 is (CH.sub.2).sub.m OR.sup.16, C.sub.1 -C.sub.4 alkyl,
allyl, propargyl, (CH.sub.2).sub.m R.sup.13, or --(CH.sub.2).sub.m
OC(O)R.sup.16 ;
X is halogen, S(O).sub.2 R.sup.8, SR.sup.8, halomethyl,
--(CH.sub.2).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, --C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.4
-C.sub.10 cycloalkylalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2
-C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, C.sub.3 -C.sub.6
cycloalkyl, nitro, thio-(C.sub.1 -C.sub.10)-alkyl,
--C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is independently selected at each occurrence from the group
consisting of hydrogen, halogen, S(O).sub.n R.sup.8, halomethyl,
--(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p
NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1
-C.sub.10 alkoxy, C.sub.3 -C.sub.6 cycloalkyl, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl, C.sub.1
-C.sub.6 alkoxy, --(CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p
S(O).sub.n R.sup.8, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15,
C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2
-C.sub.10 alkynyl, cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro,
amino-(C.sub.2 -C.sub.10)-alkyl, thio-(C.sub.2 -C.sub.10)-alkyl,
SO.sub.n (R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or
C(.dbd.O)NR.sup.14 R.sup.15, where substitution by R.sup.18 can
occur on any carbon containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, (C.sub.4
-C.sub.12)-cycloalkylalkyl, --(CH.sub.2).sub.k R.sup.13,
(CHR.sup.16).sub.p OR.sup.8, --(C.sub.1 -C.sub.6 alkyl)-aryl,
phenyl, heteroaryl, --S(O).sub.z -aryl or --(C.sub.1 -C.sub.6
alkyl)-heteroaryl, wherein the aryl or heteroaryl groups are
optionally substituted with 1-3 groups selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
-C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro,
carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), cyano, S(O).sub.z
--(C.sub.1 -C.sub.6 alkyl); or can be taken together to form
--(CH.sub.2).sub.q A(CH.sub.2).sub.r --, optionally substituted
with 0-3 R.sup.17 ;
A is CH.sub.2, O, NR.sup.25, C(.dbd.O), S(O).sub.n,
N(C(.dbd.O)R.sup.17), N(R.sup.19), C(H)(NR.sup.14 R.sup.15),
C(H)(OR.sup.20), C(H)(C(.dbd.O)R.sup.21), N(S(O).sub.n
R.sup.21);
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.t R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; --NR.sup.6 R.sup.7 ; aryl; heteroaryl;
--NR.sup.16 (CH.sub.2).sub.n NR.sup.6 R.sup.7 ; --(CH.sub.2).sub.k
R.sup.25 ; and (CH.sub.2).sub.t heteroaryl or (CH.sub.2).sub.t
aryl, either of which can be optionally substituted with 1-3 groups
selected from the group consisting of hydrogen, halogen, C.sub.1
-C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1
-C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl) N(C.sub.1 -C.sub.6
alkyl).sub.2, nitro, carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl),
cyano, and S(O).sub.z (C.sub.1 -C.sub.6 -alkyl);
R.sup.9 is independently selected at each occurrence from R.sup.10,
hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.2 -C.sub.4 alkenyl, phenyl substituted with 0-3 R.sup.18, and
--(C.sub.1 -C.sub.6 alkyl)-aryl substituted with 0-3 R.sup.18 ;
R.sup.10, R.sup.16, R.sup.23, and R.sup.24 are independently
selected at each occurrence from hydrogen or C.sub.1 -C.sub.4
alkyl;
R.sup.11 is C.sub.1 -C.sub.4 alkyl substituted with 0-3 groups
chosen from the following: keto, amino, sulfhydryl, hydroxyl,
guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl, and
indolinyl, or, when taken together with an adjacent R.sup.10, are
(CH.sub.2).sub.t ;
R.sup.12 is hydrogen or an appropriate amine protecting group for
nitrogen or an appropriate carboxylic acid protecting group for
carboxyl;
R.sup.13 is independently selected at each occurrence from the
group consisting of CN, OR.sup.19, SR.sup.19, and C.sub.3 -C.sub.6
cycloalkyl;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.4 -C.sub.10
cycloalkyl-alkyl, and R.sup.19 ;
R.sup.17 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, NR.sup.23 R.sup.24, and (C.sub.1 -C.sub.6)
alkyl (C.sub.1 -C.sub.4) alkoxy;
R.sup.18 is independently selected at each occurrence from the
group consisting of R.sup.10, hydroxy, halogen, C.sub.1 -C.sub.2
haloalkyl, C.sub.1 -C.sub.4 alkoxy, C(.dbd.O)R.sup.24, and
cyano;
R.sup.19 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6
cycloalkyl, (CH.sub.2).sub.w R.sup.22, and phenyl substituted with
0-3 R.sup.18 ;
R.sup.20 is independently selected at each occurrence from the
group consisting of R.sup.10, C(.dbd.O)R.sup.31, and C.sub.2
-C.sub.4 alkenyl;
R.sup.21 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, NR.sup.23
R.sup.24, and hydroxyl;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, OR.sup.24, SR.sup.24, NR.sup.23
R.sup.24, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
--S(O).sub.n R.sup.31, and --C(.dbd.O)R.sup.25 ;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, and pyridyl;
R.sup.25a, which can be optionally substituted with 0-3 R.sup.17,
is independently selected at each occurrence from the group
consisting of H and R.sup.25 ;
R.sup.27 is independently selected at each occurrence from the
group consisting of C.sub.1 C.sub.3 alkyl, C.sub.2 -C.sub.4
alkenyl, C.sub.2-4 alkynl, C.sub.2-4 alkoxy, aryl, nitro, cyano,
halogen, and phenyloxy;
R.sup.31 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7
cycloalkyl, C.sub.4 -C.sub.10 cycloalkyl-alkyl, and aryl-(C.sub.1
-C.sub.4) alkyl;
k, m, and r are independently selected at each occurrence from
1-4;
n is independently selected at each occurrence from 0-2;
p, q, and z are independently selected at each occurrence from
0-3;
t and w are independently selected at each occurrence from 1-6;
provided that when K and L are both CH, then
(A) when R.sup.2 is H and R.sup.1 and R.sup.3 are methyl,
(1) and R.sup.4 is methyl, then
(a) R.sup.5 can not be C.sub.1 -C.sub.6 alkyl when X is OH and X'
is H;
(b) R.sup.5 can not be (CHR.sup.16).sub.p NR.sup.14 R.sup.15
wherein p is 0 when X and X' are --OCH.sub.3 ; and
(c) R.sup.5 can not be (CHR .sup.16).sub.p NR.sup.14 R.sup.15 when
X and X' are --OCH.sub.2 CH.sub.3 ; and
(2) and R.sup.4 is ethyl, then
(a) R.sup.5 can not be (CHR.sup.16).sub.p NR.sup.14 R.sup.15 when X
and X' are --OCH.sub.3 ;
(b) R.sup.5 can not be (CHR.sup.16).sub.p OR.sup.18 with p=0 and
R.sup.18 =H when X is Br and X' is OH; and
(c) R.sup.5 can not be C1-C6 alkyl substituted with OH; or
(CHR.sup.16).sub.p NR.sup.14 R.sup.15 wherein R.sup.16 =H and p=1-3
and R.sup.14 and R.sup.15 are H or C.sub.1 -C.sub.6 alkyl when X is
--SCH.sub.3 and X' is H;
(B) when R.sup.2 is H, R.sup.4 is ethyl, R.sup.5 is iso-propyl, X
is Br, X' is H, and
(1) R.sup.1 is CH.sub.3 ; then
(a) R.sup.3 can not be OR.sup.8, CO.sub.2 R.sup.12,
C(.dbd.O)NR.sup.6 R.sup.7, (CH.sub.2).sub.k OR.sub.8 ;
(CHR.sup.16).sub.k NR.sup.6 R.sup.7 ;
(2) R.sup.1 is --CH.sub.2 CH.sub.2 CH.sub.3 then R.sup.3 can not be
C.sub.1 -C.sub.6 alkyl;
further provided that when X' is H, and K and L are both CH,
then
(D) when R.sup.2 is H or C.sub.1 -C.sub.3 alkyl; R.sup.4 is C.sub.1
-C.sub.4 alkyl; R.sup.5, X and/or X' are OH, halo, CF.sub.3,
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4
alkylthio, cyano, amino, carbamoyl, or C.sub.1 -C.sub.4 alkanoyl;
and R.sup.1 is C.sub.1 -C.sub.4 alkyl, then R.sup.3 can not be
--NH(substituted phenyl) or --N (C.sub.1 -C.sub.4 alkyl)
(substituted phenyl) and further provided that when R.sup.3 is
S(O).sub.n R.sup.8, R.sup.8 is not hydrogen;
and when R.sup.3 is --C(CN)(R.sup.25)(R.sup.16), R.sup.25 is not
pyridyl and when R.sup.3 is S(O).sub.n R.sup.8, R.sup.8 is not
H;
wherein the term "heterocycle" is defined as pyridyl, pyridinyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl,
isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl,
pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl
or octahydroisoquinolinyl, azocinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl,
pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,
2H-pyrrolyl, pyrrole, imidazolyl, pyrazolyl, isothiazolyl,
isoxazole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindole, 3H-indolyl, indolyl, 1H-indazolyl, purinyl,
4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazolyl, carbazolyl, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,
pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl;
wherein the term "aryl" is defined as phenyl, biphenyl or naphthyl;
and
wherein the term "heteroaryl" is defined as 2-, or 3-, or
4-pyridyl; 2- or 3-furyl; 2- or 3-benzofuranyl; 2-, or
3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or
4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1-
or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2- or
4- or 5-imidazolyl; 1- or 2-benzimidazolyl; 2- or 4- or
5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4-
or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2-
or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-
cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl
ring.
2. A compound of claim 1 wherein:
R.sup.1 is C.sub.1 -C.sub.4 alkyl;
R.sup.3 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.1 -C.sub.2 haloalkyl, NR.sup.6 R.sup.7, OR.sup.8,
C(.dbd.O)R.sup.9, C(.dbd.O)NR.sup.6 R.sup.7, --(CHR.sup.16).sub.k
NR.sup.6 R.sup.7, (CH.sub.2).sub.k OR.sup.8,
--(CHR.sup.16)R.sup.25, substituted C.sub.1 -C.sub.4 alkyl,
substituted C.sub.1 -C.sub.4 alkenyl, substituted C.sub.2 -C.sub.4
alkynyl, substituted C.sub.1 -C.sub.4 alkoxy, substituted C.sub.3
-C.sub.6 cycloalkyl or substituted C.sub.1 -C.sub.4 alkylamino,
where substitution by one or two R.sup.27 can occur on any
carbon-containing substituent;
R.sup.4 is C.sub.1 -C.sub.4 alkyl, allyl, or propargyl;
X is halogen, S(O).sub.2 R.sup.8, SR.sup.8, halomethyl,
--(CH.sub.2).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, --C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.4
-C.sub.10 cycloalkylalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2
-C.sub.10 alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl-(C.sub.2
-C.sub.10)-alkyl, C.sub.3 -C.sub.6 cycloalkyl, aryl-(C.sub.1
-C.sub.10)-alkoxy, nitro, thio-(C.sub.1 -C.sub.10)-alkyl,
--C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 ;
X' is independently selected at each occurrence from the group
consisting of hydrogen, halogen except when M is N, S(O).sub.n
R.sup.8, halomethyl, --(CHR.sup.16).sub.p OR.sup.8, cyano,
--(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10
alkynyl, C.sub.1 -C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl,
C.sub.3 -C.sub.6 cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy,
nitro, thio-(C.sub.1 -C.sub.10)-alkyl,
--C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 ;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl, C.sub.1
-C.sub.6 alkoxy, --(CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p
S(O).sub.n R.sup.8, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15,
C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2
-C.sub.10 alkynyl, cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro,
amino-(C.sub.2 -C.sub.10)-alkyl, thio-(C.sub.2 -C.sub.10)-alkyl,
SO.sub.n (R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or
C(.dbd.O)NR.sup.14 R.sup.15 ;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, (C.sub.4
-C.sub.12)-cycloalkylalkyl, --(CH.sub.2).sub.k R.sup.13,
(CHR.sup.16).sub.p OR.sup.8, phenyl, or --S(O).sub.z -aryl; or can
be taken together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --,
optionally substituted with 0-3 R.sup.17 ;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.t R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; or --NR.sup.6 R.sup.7 ; and
R.sup.9 is independently selected at each occurrence from R.sup.10,
C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl, or C.sub.2
-C.sub.4 alkenyl.
3. A compound of claim 1 selected from the group consisting of:
N-(2,4-dimethoxyphenyl)-N-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-cyclohexylethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methy
l-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-py
rimidinamine;
N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(.sub.2
-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidi
namine;
N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxye
thylamino)-2-pyrimidinamine;
N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbon
yl)-2-pyrimidinamine;
methyl
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarbo
xylate;
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyr
imidinecarboxamide;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazi
nylcarbonyl)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfinyl)-2-p
yrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfonyl)-2-p
yrimidinamine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4(S)-(N-methyl-2'-pyrrolid
inomethoxy)-6-methyl-2-pyrimidinamine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiazolidino-6-methyl-2-pyrimi
dinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidin
amine;
N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrim
idinamine;
N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinam
ine;
N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-py
rimidinamine;
N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinam
ine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-
2-pyrimidinamine;
N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
;
N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylam
ino)carbonyl-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino
)carbonyl)-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-m
ethylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-met
hylpyrimidinamine, hydrochloride salt;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methy
lpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymeth
yl)-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methy
lpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-meth
ylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylp
yrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-me
thylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamin
e;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine
;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-
methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-
hydroxymethyl)-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimid
inamine, hydrochloride salt;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimi
dinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methyleth
yl)-6-methylpyrimidinamine;
2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine;
and
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methylpyri
midine.
4. A compound of claim 1 selected from the group consisting of:
N-(2,4-dimethoxyphenyl)-N-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-cyclohexylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidi
namine;
N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidin
amine;
N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrim
idinamine;
N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinam
ine;
N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-py
rimidinamine;
N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
;
N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
and
N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.
5. A compound of claim 1 selected from the group consisting of:
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methy
l-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-py
rimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyri
midinamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxye
thylamino)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbon
yl)-2-pyrimidinamine;
methyl
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarbo
xylate;
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyr
imidinecarboxamide;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazi
nylcarbonyl)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfinyl)-2-p
yrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfonyl)-2-p
yrimidinamine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinam
ine;
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-
2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylam
ino)carbonyl-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino
)carbonyl)-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-m
ethylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-met
hylpyrimidinamine, hydrochloride salt;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methy
lpyrimidinamine;
N-(.sub.2
-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymethyl)
-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methy
lpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-meth
ylpyrimidinamine;
N-(.sub.2
-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-me
thylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamin
e;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine
;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-
methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-
hydroxymethyl)-6-methylpyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimid
inamine, hydrochloride salt;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimi
dinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methyleth
yl)-6-methylpyrimidinamine;
2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine;
and
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methylpyri
midine.
6. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 1.
7. A method of treating affective disorders, anxiety, or depression
in mammals in need of such treatment comprising administering to
the mammals a therapeutically effective amount of a compound of
claim 1.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds, compounds and
pharmaceutical compositions thereof, and to methods of using same
in the treatment of psychiatric disorders and neurological diseases
including major depression, anxiety-related disorders,
post-traumatic stress disorder, supranuclear palsy eating feeding
disorders, irritable bowel syndrome, immune suppression,
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, and fertility problems.
2. Description of the Related Art
Corticotropin releasing factor (herein referred to as CRF), a 41
amino acid peptide, is the primary physiological regulator of
proopiomelanocortin (POMC)-derived peptide secretion from the
anterior pituitary gland (J. Rivier et al., Proc. Nat. Acad. Sci.
(USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)). In
addition to its endocrine role at the pituitary gland,
immunohistochemical localization of CRF has demonstrated that the
hormone has a broad extrahypothalamic distribution in the central
nervous system and produces a wide spectrum of autonomic,
electrophysiological and behavioral effects consistent with a
neurotransmitter or neuromodulator role in brain (W. Vale et al.,
Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med.
2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)).
There is also evidence demonstrating that CRF may also play a
significant role in integrating the response of the immune system
to physiological, psychological, and immunological stressors (J. E.
Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci.
41:527 (1987)).
Clinical data have demonstrated that CRF may have implications in
psychiatric disorders and neurological diseases including
depression, anxiety-related disorders and eating disorders. A role
for CRF has also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy and
amyotrophic lateral sclerosis as they relate to the dysfunction of
CRF neurons in the central nervous system (for review see E. B. De
Souza, Hosp. Practice 23:59 (1988)).
In affective disorder, or major depression, the concentration of
CRF is significantly increased in the cerebral spinal fluid (CSF)
of drug-free individuals (C. B. Nemeroff et al., Science 226:1342
(1984); C. M. Banki et al. Am. J. Psychiatry 144:873 (1987); R. D.
France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al.,
Biol. Psychiatry 25:355 (1989)). Furthermore, the density of CRF
receptors is significantly decreased in the frontal cortex of
suicide victims, consistent with a hypersecretion of CRF (C. B.
Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)). In addition,
there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v.
administered) observed in depressed patients (P. W. Gold et al., Am
J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng.
J. Med. 314:1129 (1986)). Preclinical studies in rats and non-human
primates provide additional support for the hypothesis that
hypersecretion of CRF may be involved in the symptoms seen in human
depression (R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)).
There is preliminary evidence that tricyclic antidepressants can
alter CRF levels and thus modulate the number of CRF receptors in
brain (Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)).
There has also been a role postulated for CRF in the etiology of
anxiety-related disorders. CRF produces anxiogenic effects in
animals and interactions between benzodiazepine/non-benzodiazepine
anxiolytics and CRF have been demonstrated in a variety of
behavioral anxiety models (D. R. Britton et al., Life Sci. 31:363
(1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83
(1986)). Preliminary studies using the putative CRF receptor
antagonist .alpha.-helical ovine CRF (9-41) in a variety of
behavioral paradigms demonstrate that the antagonist produces
"anxiolytic-like" effects that are qualitatively similar to the
benzodiazepines (C. W. Berridge and A. J. Dunn Horm. Behav. 21:393
(1987), Brain Research Reviews 15:71 (1990)). Neurochemical,
endocrine and receptor binding studies have all demonstrated
interactions between CRF and benzodiazepine anxiolytics providing
further evidence for the involvement of CRF in these disorders.
Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both
the conflict test (K. T. Britton et al., Psychopharmacology 86:170
(1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)) and
in the acoustic startle test (N. R. Swerdlow et al.,
Psychopharmacology 88:147 (1986)) in rats. The benzodiazepine
receptor antagonist (Ro15-1788), which was without behavioral
activity alone in the operant conflict test, reversed the effects
of CRF in a dose-dependent manner while the benzodiazepine inverse
agonist (FG7142) enhanced the actions of CRF (K. T. Britton et al.,
Psychopharmacology 94:306 (1988)).
The mechanisms and sites of action through which the standard
anxiolytics and antidepressants produce their therapeutic effects
remain to be elucidated. It has been hypothesized, however, that
they are involved in the suppression of the CRF hypersecretion that
is observed in these disorders. Of particular interest is that
preliminary studies examining the effects of a CRF receptor
antagonist (.alpha.-helical CRF.sub.9-41) in a variety of
behavioral paradigms have demonstrated that the CRF antagonist
produces "anxiolytic-like" effects qualitatively similar to the
benzodiazepines (for review, see G. F. Koob and K. T. Britton, In:
Corticotropin-Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press
p.221 (1990)).
In order to study these specific cell-surface receptor proteins,
compounds must be identified that can interact with the CRF
receptor in a specific manner dictated by the pharmacological
profile of the characterized receptor. Toward that end, there is
evidence that the direct CRF antagonist compounds and compositions
of this invention, which can attenuate the physiological responses
to stress-related disorders, will have potential therapeutic
utility for the treatment of depression and anxiety-related
disorders. All of the aforementioned references are hereby
incorporated by reference.
U.S. Pat. Nos. 4,788,195 and 4,876,252 teach the synthesis of
compounds with the general formula (A): ##STR2##
The utility of these compounds is described as treatment of asthma,
allergic diseases, inflammation, and diabetes in mammals.
PCT application WO 89/01938 describes the synthesis and utility of
compounds with the formula (B): ##STR3##
These compounds can be utilized in the treatment of neurologic
diseases, having an effect of regenerating and repairing nerve
cells and improving and restoring learning and memory.
U.S. Pat. No. 4,783,459 describes the utility and synthesis of
compounds with the following general formula (C): ##STR4##
The compounds have activity as fungicides, especially against
fungal diseases of plants.
U.S. Pat. No. 4,992,438 discloses the utility and synthesis of
compounds with the following general formula: ##STR5##
The utility of these compounds is described as fungicides with a
broad spectrum activity against plant pathogenic fungi.
European Patent Application 0 013 143 A2 discloses the utility and
synthesis of compounds with the following general formula:
##STR6##
These compounds are described as pre- and post-emergence
herbicides.
U.S. Pat. No. 5,063,245 discloses a method of producing CRF
antagonism with compounds with the general formulae: ##STR7##
PCT application WO 91/18887 discloses compounds of the general
formula: ##STR8##
wherein R.sup.2 may be C.sub.1 -C.sub.4 alkyl and R.sup.3 may be
substituted phenyl, said compounds being useful for the inhibition
of gastric acid secretion.
European patent application EP 0588762 A1 discloses compounds of
the general formula: ##STR9##
wherein R.sup.4 may be C.sub.1 -C.sub.3 alkyl, said compounds being
useful as protein kinase C inhibitors and antitumor agents. The
application also generally discloses the use of these compounds for
the treatment of AIDS, atherosclerosis, and cardiovascular and
central nervous system disorders.
European patent application EP 336494 A2 discloses compounds of the
general formula: ##STR10##
wherein X may be N--R.sup.4 and R.sup.4 may be (un)substituted
alkyl, said compounds being useful as herbicides.
U.S. Pat. No. 3,988,338 discloses compounds of the general formula:
##STR11##
wherein R"" may be an optionally substituted phenyl, said compounds
having anticytokinin activity.
European patent application EP 0563001 A1 discloses compounds of
the general formula: ##STR12##
said compounds having claimed utility for the treatment of
psychosis, depression, and convulsive disorders.
European patent application EP 0155911 A1 discloses compounds of
the general formula: ##STR13##
wherein R.sup.3 may be substituted phenyl, said compounds being
useful as herbicides.
Australian patent AU 8425873 A discloses compounds of the general
formula: ##STR14##
wherein R.sup.2 may be a substituted phenyl group, said compounds
being useful as antiulcer agents.
Eswaran et al, Org. Prep. Proced. Int. 24(1):71-3, (1992),
discloses the use of related 5,7-diazaindoles as synthetic
intermediates. El-Bayouki et al, J. Heterocycl. Chem. 22(3):853-6,
(1985) discloses the use of related 5,7-diazaisoindazoles as
synthetic intermediates.
The compounds and methods of the present invention provide the
methodology for the production of specific high-affinity compounds
capable of inhibiting the action of CRF at its receptor protein in
the brain. These compounds should be useful in the treatment of a
variety of neurodegenerative, neuropsychiatric and stress-related
disorders such as irritable bowel syndrome, immune suppression.
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, and fertility problems. It is further asserted that this
invention may provide compounds and pharmaceutical compositions
suitable for use in such a method. Further advantages of this
invention will be clear to one skilled in the art from the reading
of the description that follows.
SUMMARY OF THE INVENTION
The present invention relates to compositions and methods of use
and preparation of N-alkyl-N-aryl-pyrimidinamines and derivatives
thereof. These compounds interact with and have antagonist activity
at the CRF receptor and would thus have some therapeutic effect on
psychiatric disorders and neurological diseases including major
depression, anxiety-related disorders, post-traumatic stress and
eating disorders, supranuclear palsy, irritable bowel syndrome,
immune suppression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, drug and alcohol withdrawal symptoms, drug
addiction, inflammatory disorders, and fertility problems.
Novel compounds of this invention include compounds of formula:
##STR15##
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y
is CR.sup.3a, N, or CR.sup.29 ;
when Y is CR.sup.3a or N:
R.sup.1 is independently selected at each occurrence from the group
consisting of C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl,
C.sub.2 -C.sub.4 alkynyl, halogen, C.sub.1 -C.sub.2 haloalkyl,
NR.sup.6 R.sup.7, OR.sup.8, and S(O).sub.n R.sup.8 ;
R.sup.3 is C.sub.1 -C.sub.4 alkyl, aryl, C.sub.3 -C.sub.6
cycloalkyl, C.sub.1 -C.sub.2 haloalkyl, halogen, nitro, NR.sup.6
R.sup.7, OR.sup.8, S(O).sub.n R.sup.8, C(.dbd.O)R.sup.9,
C(.dbd.O)NR.sup.6 R.sup.7, C(.dbd.S)NR.sup.6 R.sup.7,
--(CHR.sup.16).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k OR.sup.8,
C(.dbd.O)NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12,
--C(OH)(R.sup.25)(R.sup.25a), --(CH.sub.2).sub.p S(O).sub.n -alkyl,
--(CHR.sup.16)R.sup.25, --C(CN)(R.sup.25)(R.sup.16) provided that
R.sup.25 is not --NH-containing rings, --C(.dbd.O)R.sup.25,
--CH(CO.sub.2 R.sup.16).sub.2, NR.sup.10
C(.dbd.O)CH(R.sup.11)NR.sup.10 R.sup.12, NR.sup.10
CH(R.sup.11)CO.sub.2 R.sup.12 ; substituted C.sub.1 -C.sub.4 alkyl,
substituted C.sub.2 -C.sub.4 alkenyl, substituted C.sub.2 -C.sub.4
alkynyl, substituted C.sub.1 -C.sub.4 alkoxy, aryl-(substituted
C.sub.1 -C.sub.4) alkyl, aryl-(substituted C.sub.1 -C.sub.4)
alkoxy, substituted C.sub.3 -C.sub.6 cycloalkyl, amino-(substituted
C.sub.1 -C.sub.4) alkyl, substituted C.sub.1 -C.sub.4 alkylamino,
where substitution by R.sup.27 can occur on any carbon containing
substituent; 2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl,
2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl,
phenyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl,
chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,
imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,
isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl
benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl,
.beta.-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl,
thiophenyl, triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
J, K, and L are independently selected at each occurrence from the
group of N, CH, and CX';
M is CR.sup.5 or N;
V is CR.sup.1a or N;
Z is CR.sup.2 or N;
R.sup.1a, R.sup.2, and R.sup.3a are independently selected at each
occurrence from the group consisting of hydrogen, halo, halomethyl,
C.sub.1 -C.sub.3 alkyl, and cyano;
R.sup.4 is (CH.sub.2).sub.m OR.sup.16, C.sub.1 -C.sub.4 alkyl,
allyl, propargyl, (CH.sub.2).sub.m R.sup.13, or --(CH.sub.2).sub.m
OC(O)R.sup.16 ;
X is halogen, S(O).sub.2 R.sup.8, SR.sup.8, halomethyl,
--(CH.sub.2).sub.p OR.sup.8, --OR.sup.8, cyano,
--(CHR.sup.16).sub.p NR.sup.14 R.sup.15, --C(.dbd.O)R.sup.8,
C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10
alkoxy, aryl-(C.sub.2 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is independently selected at each occurrence from the group
consisting of hydrogen, halogen, S(O).sub.n R.sup.8, halomethyl,
--(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p
NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1
-C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, and --C(.dbd.O)NR.sup.14 R.sup.15, where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl,
--(CHR.sup.16).sub.p OR.sup.8, --(CHR.sup.16).sub.p S(O).sub.n
R.sup.8, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3 14
C.sub.6 cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10
alkynyl, aryl-(C.sub.2 -C.sub.10)-alkyl, aryl-(C.sub.1
-C.sub.10)-alkoxy, cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro,
amino-(C.sub.1 -C.sub.10)-alkyl, thio-(C.sub.2 -C.sub.10)-alkyl,
SO.sub.n (R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or
--C(.dbd.O)NR.sup.14 R.sup.15, where substitution by R.sup.18 can
occur on any carbon containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, (C.sub.4
-C.sub.12)-cycloalkylalkyl, --(CH.sub.2).sub.k R.sup.13,
(CHR.sup.16).sub.p OR.sup.8, --(C.sub.1 -C.sub.6 alkyl)-aryl,
heteroaryl, aryl, --S(O).sub.2 -aryl or --(C.sub.1 -C.sub.6
alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are
optionally substituted with 1-3 groups selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
-C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro,
carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), cyano, and S(O).sub.z
--(C.sub.1 -C.sub.6 -alkyl); or can be taken together to form
--(CH.sub.2).sub.q A(CH.sub.2).sub.r --, optionally substituted
with 0-3 R.sup.17 ; or, when considered with the commonly attached
nitrogen, can be taken together to form a heterocycle, said
heterocycle being substituted on carbon with 1-3 groups consisting
of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, or C.sub.1 -C.sub.6
alkoxy;
A is CH.sub.2, O, NR.sup.25, C(.dbd.O), S(O).sub.n,
N(C(.dbd.O)R.sup.17), N(R.sup.19), C(H)(NR.sup.14 R.sup.15),
C(H)(OR.sup.20), C(H)(C(.dbd.O)R.sup.21), or N(S(O).sub.n
R.sup.21);
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.t R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; --NR.sup.6 R.sup.7 ; aryl; --NR.sup.16
(CH.sub.2).sub.n NR.sup.6 R.sup.7 ; --(CH.sub.2).sub.k R.sup.25 ;
and (CH.sub.2).sub.t heteroaryl or (CH.sub.2).sub.t aryl, either of
which can optionally be substituted with 1-3 groups selected from
the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6
alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6
alkyl).sub.2, nitro, carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl),
cyano, and S(O).sub.z (C.sub.1 -C.sub.6 -alkyl);
R.sup.9 is independently selected at each occurrence from R.sup.10,
hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.2 -C.sub.4 alkenyl, aryl substituted with 0-3 R.sup.18, and
--(C.sub.1 -C.sub.6 alkyl)-aryl substituted with 0-3 R.sup.18 ;
R.sup.10, R.sup.16, R.sup.23, and R.sup.24 are independently
selected at each occurrence from hydrogen or C.sub.1 -C.sub.4
alkyl;
R.sup.11 is C.sub.1 -C.sub.4 alkyl substituted with 0-3 groups
chosen from the following: keto, amino, sulfhydryl, hydroxyl,
guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl,
indolinyl,
or, when taken together with an adjacent R.sup.10, are
(CH.sub.2).sub.t ;
R.sup.12 is hydrogen or an appropriate amine protecting group for
nitrogen or an appropriate carboxylic acid protecting group for
carboxyl;
R.sup.13 is independently selected at each occurrence from the
group consisting of CN, OR.sup.19, SR.sup.19, and C.sub.3 -C.sub.6
cycloalkyl;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.4 -C.sub.10
cycloalkyl-alkyl, and R.sup.19 ;
R.sup.17 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, NR.sup.23 R.sup.24, and (C.sub.1 -C.sub.6)
alkyl (C.sub.1 -C.sub.4) alkoxy;
R.sup.18 is independently selected at each occurrence from the
group consisting of R.sup.10, hydroxy, halogen, C.sub.1 -C.sub.2
haloalkyl, C.sub.1 -C.sub.4 alkoxy, C(.dbd.O)R.sup.24, and
cyano;
R.sup.19 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6
cycloalkyl, (CH.sub.2).sub.w R.sup.22, and aryl substituted with
0-3 R.sup.18 ;
R.sup.20 is independently selected at each occurrence from the
group consisting of R.sup.10, C(.dbd.O)R.sup.31, and C.sub.2
-C.sub.4 alkenyl;
R.sup.21 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, NR.sup.23
R.sup.24, and hydroxyl;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, OR.sup.24, SR.sup.24, NR.sup.23
R.sup.24, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
--S(O).sub.n R.sup.31, and --C(.dbd.O)R.sup.25 ;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,
4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, 1H-indazolyl,
2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,
4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl,
benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,
isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl,
isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl,
oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,
pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl, tetrazolyl,
thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; and
1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which
can be substituted with 0-3 groups chosen from keto and C.sub.1
-C.sub.4 alkyl;
R.sup.25a, which can be optionally substituted with 0-3 R.sup.17,
is independently selected at each occurrence from the group
consisting of H and R.sup.25 ;
R.sup.27 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.4
alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.2 -C.sub.4 alkoxy, aryl,
nitro, cyano, halogen, aryloxy, and heterocycle optionally linked
through O;
R.sup.31 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7
cycloalkyl, C.sub.4 -C.sub.10 cycloalkyl-alkyl, and aryl-(C.sub.1
-C.sub.4) alkyl;
k, m, and r are independently selected at each occurrence from
1-4;
n is independently selected at each occurrence from 0-2;
p, q, and z are independently selected at each occurrence from
0-3;
t and w are independently selected at each occurrence from 1-6,
provided that when J is CX' and K and L are both CH, and M is
CR.sup.5, then
(A) when V and Y are N and Z is CH and R.sup.1 and R.sup.3 are
methyl,
(1) and R.sup.4 is methyl, then
(a) R.sup.5 can not be methyl when X is OH and X' is H;
(b) R.sup.5 can not be --NHCH.sub.3 or --N(CH.sub.3).sub.2 when X
and X' are --OCH.sub.3 ; and
(c) R.sup.5 can not be --N(CH.sub.3).sub.2 when X and X' are
--OCH.sub.2 CH.sub.3 ;
(2) and R.sup.4 is ethyl, then
(a) then R.sup.5 can not be methylamine when X and X'are
--OCH.sub.3 ;
(b) R.sup.5 can not be OH when X is Br and X' is OH; and
(c) R.sup.5 can not be --CH.sub.2 OH or --CH.sub.2
N(CH.sub.3).sub.2 when X is --SCH3 and X' is H;
(B) when V and Y are N, Z is CH, R.sup.4 is ethyl, R.sup.5 is
iso-propyl, X is Br, X' is H, and
(1) R.sup.1 is CH.sub.3, then
(a) R.sup.3 can not be OH, piperazin-1-yl, --CH.sub.2
-piperidin-1-yl, --CH.sub.2 --(N-4-methylpiperazin-1-yl),
--C(O)NH-phenyl, --CO.sub.2 H, --CH.sub.2 O-(4-pyridyl),
--C(O)NH.sub.2, 2-indolyl, --CH.sub.2 O-(4-carboxyphenyl),
--N(CH.sub.2 CH.sub.3)(2-bromo-4-isopropylphenyl);
(2) R.sup.1 is --CH.sub.2 CH.sub.2 CH.sub.3 then R.sup.3 can not be
--CH.sub.2 CH.sub.2 CH.sub.3 ;
(C) when V, Y and Z are N, R.sup.4 is ethyl, and
(1) R.sup.5 is iso-propyl, X is bromo, and X' is H, then
(a) R.sup.3 can not be OH or --OCH.sub.2 CN when R.sup.1 is
CH.sub.3 ; and
(b) R.sup.3 can not be --N(CH.sub.3).sub.2 when R.sup.1 is
--N(CH.sub.3).sub.2 ;
(2) R.sup.5 is --OCH--, X is --OCH.sub.3, and X' is H, then R.sup.3
and R.sup.1 can not both be chloro;
further provided that when J, K, and L are all CH and M is
CR.sup.5, then
(D) at least one of V, Y, and Z must be N;
(E) when V is CR.sup.1a, Z and Y can not both be N;
(F) when Y is CR.sup.3a, Z and V can not both be N;
(G) when Z is CR.sup.2, V and Y must both be N;
(H) Z can be N only when both V and Y are N or when V is CR.sup.1a
and Y is CR.sup.3a ;
(I) when V and Y are N, Z is CR.sup.2, and R.sup.2 is H or C.sub.1
-C.sub.3 alkyl, and R.sup.4 is C.sub.1 -C.sub.3 alkyl, R.sup.3 can
not be 2-pyridinyl, indolyl, indolinyl, imidazolyl, 3-pyridinyl,
4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;
(J) when V and Y are N; Z is CR.sup.2 ; R.sup.2 is H or C.sub.1
-C.sub.3 alkyl; R.sup.4 is C.sub.1 -C.sub.4 alkyl; R.sup.5, X,
and/or X' are OH, halo, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1
-C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, cyano, amino,
carbamoyl, or C.sub.1 -C.sub.4 alkanoyl; and R.sup.1 is C.sub.1
-C.sub.4 alkyl, then R.sup.3 can not be --NH(substituted phenyl) or
--N(C.sub.1 -C.sub.4 alkyl)(substituted phenyl);
and wherein, when Y is CR.sup.29 :
J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R.sup.3, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.16, R.sup.18, R.sup.19,
R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.27 are as defined
above and R.sup.25a, in addition to being as defined above, can
also be C.sub.1 -C.sub.4 alkyl, but
V is N;
R.sup.1 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl,
C.sub.2 -C.sub.4 alkynyl, C.sub.2 -C.sub.4 alkoxy, halogen, amino,
methylamino, dimethylamino, aminomethyl, or
N-methylaminomethyl;
R.sup.2 is independently selected at each occurrence from the group
consisting of hydrogen, halo, C.sub.1 -C.sub.3 alkyl, nitro, amino,
and --CO.sub.2 R.sup.10 ;
R.sup.4 is taken together with R.sup.29 to form a 5-membered ring
and is --C(R.sup.28).dbd. or --N.dbd. when R.sup.29 is
--C(R.sup.30).dbd. or --N.dbd., or --CH(R.sup.28)-- when R.sup.29
is --CH(R.sup.30)--;
X is Cl, Br, I, S(O).sub.n R.sup.8, OR.sup.8, halomethyl,
--(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p
NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1
-C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10 )-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is hydrogen, Cl, Br, I, S(O).sub.n R.sup.8, --(CHR.sup.16).sub.p
OR.sup.8, halomethyl, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10,
alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.2 -C.sub.10)-alkoxy, nitro, thio-(C.sub.2
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C1-C3 haloalkyl, C.sub.1 -C.sub.6 alkoxy,
(CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p S(O).sub.n R.sup.8,
(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, aryl-(C.sub.2
-C.sub.10)-alkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, cyano, C.sub.3
-C.sub.6 cycloalkoxy, nitro, amino-(C.sub.1 -C.sub.10)-alkyl,
thio-(C.sub.1 -C.sub.10)-alkyl, SO.sub.n (R.sup.8),
C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8
R.sup.15 where substitution by R.sup.18 can occur on any carbon
containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.k R.sup.13, (C.sub.4
-C.sub.12)-cycloalkylalkyl, C.sub.1 -C.sub.6 alkoxy, --(C.sub.1
-C.sub.6 alkyl)-aryl, heteroaryl, aryl, --S(O).sub.z -aryl or
--(C.sub.1 -C.sub.6 alkyl)-heteroaryl or aryl wherein the aryl or
heteroaryl groups are optionally substituted with 1-3 groups
selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
-C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro,
carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), and cyano; or can be
taken together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --,
optionally substituted with 0-3 R.sup.17 ; or, when considered with
the commonly attached nitrogen, can be taken together to form a
heterocycle, said heterocycle being substituted on carbon with 1-3
groups consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, or
C.sub.1 -C.sub.6 alkoxy;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, --(C.sub.4
-C.sub.12) cycloalkylalkyl, (CH.sub.2).sub.t R.sup.22, C.sub.3
-C.sub.10 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)-aryl, heteroaryl,
--NR.sup.16, --N(CH.sub.2).sub.n NR.sup.6 R.sup.7 ;
--(CH.sub.2).sub.k R.sup.25, --(C.sub.1 -C.sub.6 alkyl)-heteroaryl
or aryl optionally substituted with 1-3 groups selected from
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6
alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro, carboxy, CO.sub.2
(C.sub.1 -C.sub.6 alkyl), and cyano;
R.sup.9 is independently selected at each occurrence from R.sup.10,
hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.2 -C.sub.4 alkenyl, and aryl substituted with 0-3 R.sup.18
;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.6 cycloalkyl, (CH.sub.2).sub.t R.sup.22, and aryl
substituted with 0-3 R.sup.18 ;
R.sup.17 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, and NR.sup.23 R.sup.24 ;
R.sup.20 is independently selected at each occurrence from the
group consisting of R.sup.10 and C(.dbd.O)R.sup.31 ;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, OR.sup.24, SR.sup.24, NR.sup.23
R.sup.24, C.sub.3 -C.sub.6 cycloalkyl, --S(O).sub.n R.sup.31, and
--C(.dbd.O)R.sup.25 ;
R.sup.26 is hydrogen or halogen:
R.sup.28 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl,
C.sub.2 -C.sub.4 alkynyl, hydrogen, C.sub.1 -C.sub.2 alkoxy,
halogen, or C.sub.2 -C.sub.4 alkylamino;
R.sup.29 is taken together with R.sup.4 to form a five membered
ring and is: --CH(R.sup.30)-- when R.sup.4 is --CH(R.sup.28)--,
--C(R.sup.30).dbd. or --N.dbd. when R.sup.4 is --C(R.sup.28).dbd.
or --N.dbd.;
R.sup.30 is hydrogen, cyano, C.sub.1 -C.sub.2 alkyl, C.sub.1
-C.sub.2 alkoxy, halogen, C.sub.1 -C.sub.2 alkenyl, nitro, amido,
carboxy, or amino;
R.sup.31 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, or
aryl-(C.sub.1 -C.sub.4) alkyl;
provided that when J, K, and L are all CH, M is CR.sup.5, Z is CH,
R.sup.3 is CH.sub.3, R.sup.28 is H, R.sup.5 is iso-propyl, X is Br,
X' is H, and R.sup.1 is CH.sub.3, then R.sup.30 can not be H,
--CO.sub.2 H, or --CH.sub.2 NH.sub.2 ;
and further provided that when J, K and L are all CH; M is CR.sup.5
; Z is N; and
(A) R.sup.29 is --C(R.sup.1).dbd.; then one of R.sup.28 or R.sup.30
is hydrogen;
(B) R.sup.29 is N; then R.sup.3 is not halo, NH.sub.2, NO.sub.2,
CF.sub.3, CO.sub.2 H, CO.sub.2 -alkyl, alkyl, acyl, alkoxy, OH, or
--(CH.sub.2).sub.m Oalkyl;
(C) R.sup.29 is N; then R.sup.28 is not methyl if X or X' are bromo
or methyl and R.sup.5 is nitro; or
(D) R.sup.29 is N, and R.sup.1 is CH.sub.3 and R.sup.3 is amino;
then R.sup.5 is not halogen or methyl.
Preferred compounds of this invention are those compounds of
Formula I wherein,
Y is CR.sup.3a or N:
R.sup.3 is C.sub.1 -C.sub.4 alkyl, aryl, halogen, C.sub.1 -C.sub.2
haloalkyl, nitro, NR.sup.6 R.sup.7, OR.sup.8, SR.sup.8,
C(.dbd.O)R.sup.9, C(.dbd.O)NR.sup.6 R.sup.7, C(.dbd.S)NR.sup.6
R.sup.7, (CH.sub.2).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k
OR.sup.8, C(.dbd.O)NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12,
--(CHR.sup.16).sub.p OR.sup.8, --C(OH)(R.sup.25)(R.sup.25a),
--(CH.sub.2).sub.p S(O).sub.n -alkyl, --C(CN)(R.sup.25)(R.sup.16)
provided that R.sup.25 is not an --NH-- containing ring,
--C(.dbd.O)R.sup.25, --CH(CO.sub.2 R.sup.16).sub.2, NR.sup.10
C(.dbd.O)CH(R.sup.11)NR.sup.10 R.sup.12 ; substituted C.sub.1
-C.sub.4 alkyl, substituted C.sub.2 -C.sub.4 alkenyl, substituted
C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, substituted
C.sub.1 -C.sub.4 alkoxy, aryl-(substituted C.sub.1 -C.sub.4) alkyl,
aryl-(substituted C.sub.1 -C.sub.4) alkoxy, substituted C.sub.3
-C.sub.6 cycloalkyl, amino-(substituted C.sub.1 -C.sub.4)alkyl,
substituted C.sub.1 -C.sub.4 alkylamino, where substitution by
R.sup.27 can occur on any carbon containing substituent;
2-pyridinyl, indolinyl, indolyl, pyrazoyl, imidazolyl, 3-pyridinyl,
4-pyridinyl, furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
or 5-methyl-2-thienyl, azetidinyl, 2-pyrrolidonyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,
azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,
imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,
isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl,
pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,
quinolinyl, quinoxalinyl, quinuclidinyl, .beta.-carbolinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, thiazolyl, triazinyl; or 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
J, K, and L are independently selected at each occurrence from the
group consisting of CH and CX';
M is CR.sup.5 ;
R.sup.1a, R.sup.2, and R.sup.3a are independently selected at each
occurrence from the group consisting of hydrogen, halo, methyl, or
cyano;
X is halogen, S(O).sub.2 R.sup.8, SR.sup.8 halomethyl,
(CH.sub.2).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10
alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
-C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is hydrogen, halogen, S(O).sub.n R.sup.8, halomethyl,
(CH.sub.2).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10
alkoxy, aryl-(C.sub.1 -C.sub.10 -alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16) --C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl, C.sub.1
-C.sub.6 alkoxy, (CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p
S(O).sub.n R.sup.8, (CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3
-C.sub.6 cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10
alkynyl, aryl-(C.sub.2 -C.sub.10)-akyl, aryl-(C.sub.2
-C.sub.10)-alkoxy, cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro,
amino-(C.sub.2 -C.sub.10)-alkyl, thio-(C.sub.2 -C.sub.10)-alkyl,
SO.sub.n (R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or
C(.dbd.O)NR.sup.14 R.sup.15 where substitution by R.sup.18 can
occur on any carbon containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, cycloalkylalkyl, --(CH.sub.2).sub.k
R.sup.13, C.sub.1 -C.sub.6 alkoxy, --(CHR.sup.16).sub.p OR.sup.8,
--(C.sub.1 -C.sub.6 alkyl)-aryl, aryl, heteroaryl, --(C.sub.1
-C.sub.6 alkyl)-heteroaryl or aryl, wherein the aryl or heteroaryl
groups are optionally substituted with 1-3 groups selected from
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl),
N(C.sub.1 -C.sub.6 alkyl).sub.2, carboxy, CO.sub.2 (C.sub.1
-C.sub.6 alkyl), cyano, or can be taken together to form
--(CH.sub.2).sub.q A(CH.sub.2).sub.r --, optionally substituted
with 0-3 R.sup.17, or, when considered with the commonly attached
nitrogen, can be taken together to form a heterocycle, said
heterocycle being substituted on carbon with 1-3 groups consisting
of hydrogen, C.sub.1 -C.sub.6 alkyl, (C.sub.1
-C.sub.6)alkyl(C.sub.1 -C.sub.4)alkoxy, and C.sub.1 -C.sub.6
alkoxy;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.t R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; --NR.sup.6 R.sup.7 ; aryl; --NR.sup.16
(CH.sub.2).sub.n NR.sup.6 R.sup.7 ; --(CH.sub.2).sub.k R.sup.25 ;
and CH.sub.2).sub.t heteroaryl or (CH.sub.2).sub.t aryl, either of
which can optionally be substituted with 1-3 groups selected from
the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkoxy, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2,
carboxy, and CO.sub.2 (C.sub.1 -C.sub.6 alkyl);
R.sup.10 is hydrogen;
R.sup.13 is independently selected at each occurrence from the
group consisting of OR.sup.19, SR.sup.19, and C.sub.3 -C.sub.6
cycloalkyl;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.6 cycloalkyl, and C.sub.4 -C.sub.10
cycloalkyl-alkyl;
R.sup.17 is independently selected at each occurrence from the
group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1
-C.sub.4 alkoxy, and (C.sub.1 -C.sub.6)alkyl(C.sub.1
-C.sub.4)alkoxy;
R.sup.19 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6
cycloalkyl, and aryl substituted with 0-3 R.sup.18 ;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, OR.sup.24 SR.sup.24, NR.sup.23 R.sup.24,
C.sub.3 -C.sub.6 cycloalkyl, --S(O).sub.n R.sup.31, and
--C(.dbd.O)R.sup.25 ;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,
4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl, chromanyl,
chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl,
indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
quinoxalinyl, quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl,
tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
R.sup.25a, which can be optionally substituted with 0-3 R.sup.17,
is independently selected at each occurrence from the group
consisting of H, phenyl, pyrazolyl, imidazolyl,
2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, azocinyl, benzofuranyl, benzothiophenyl,
carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
furazanyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,
isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,
piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,
pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl, tetrazolyl,
thiazolyl, thiophenyl, triazinyl; and 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
t is independently selected at each occurrence from 1-3; and
w is 1-3.
Other preferred compounds of this invention are those compounds of
Formula I wherein,
Y is CR.sup.29 ;
Z is CR.sup.2 ;
R.sup.1 is methyl, amino, chloro, or methylamino;
R.sup.2 is hydrogen;
R.sup.3 is C.sub.1 -C.sub.4 alkyl, aryl, halogen, nitro, NR.sup.6
R.sup.7, OR.sup.8, SR.sup.8, C(.dbd.O)R.sup.9, C(.dbd.O)NR.sup.6
R.sup.7, (CH.sub.2).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k
OR.sup.8, --C(OH)(R.sup.25)(R.sup.25a), --(CH.sub.2).sub.p
S(O).sub.n -alkyl, --C(.dbd.O)R.sup.25, --CH(CO.sub.2
R.sup.16).sub.2 ; substituted C.sub.1 -C.sub.4 alkyl, substituted
C.sub.2 -C.sub.4 alkenyl, substituted C.sub.2 -C.sub.4 alkynyl,
C.sub.3 -C.sub.6 cycloalkyl, substituted C.sub.1 -C.sub.4 alkoxy,
aryl-(substituted C.sub.1 -C.sub.4) alkyl, aryl-(substituted
C.sub.1 -C.sub.4) alkoxy, substituted C.sub.3 -C.sub.6 cycloalkyl,
amino-(substituted C.sub.1 -C.sub.4) alkyl, substituted C.sub.1
-C.sub.4 alkylamino, or is N-linked piperidinyl, piperazinyl,
morpholino, thiomorpholino, imidazolyl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, where substitution by R.sup.27 can occur on any carbon
containing substituent;
J, K, and L are independently selected at each occurrence from the
group consisting of CH and CX';
M is CR.sup.5 ;
R.sup.4 is taken together with R.sup.29 to form a five membered
ring and is --CH.dbd.;
X is Br, I, S(O).sub.n R.sup.8, OR.sup.8, NR.sup.14 R.sup.15,
R.sup.18 substituted alkyl, or amino-(C.sub.1 -C.sub.2) alkyl;
X' is hydrogen, Br, I, S(O).sub.n R.sup.8, OR.sup.8, NR.sup.14
R.sup.15, R.sup.18 substituted alkyl, or amino-(C.sub.1 -C.sub.2)
alkyl;
R.sup.5 is independently selected at each occurrence from the group
consisting of halogen, -C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4
-alkyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
(CHR.sup.16).sub.p OR.sup.8, --NR.sup.14 R.sup.15,
(CHR.sup.16).sub.p S(O).sub.n R.sup.8, (CHR.sup.16).sub.p NR.sup.14
R.sup.15, C.sub.3 -C.sub.6 cycloalkyl, C(.dbd.O)R.sup.8, and
C(.dbd.O)NR.sup.8 R.sup.15 ; R.sup.6 and R.sup.7 are independently
selected at each occurrence from the group consisting of hydrogen,
C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
--(CH.sub.2).sub.k R.sup.13, (C.sub.3 -C.sub.6)cycloalkyl-(C.sub.1
-C.sub.6)alkyl, --(C.sub.1 -C.sub.6 alkyl)-aryl, heteroaryl,
--(C.sub.1 -C.sub.6 alkyl)-heteroaryl or aryl, wherein the aryl or
heteroaryl groups are optionally substituted with 1-3 groups
selected from hydrogen, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2
alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.2 alkyl), NH(C.sub.1
-C.sub.2 alkyl), and N(C.sub.1 -C.sub.2 alkyl).sub.2, or can be
taken together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --,
optionally substituted with 0-2 R.sup.17, or, when considered with
the commonly attached nitrogen, can be taken together to form a
heterocycle, said heterocycle being substituted on carbon with 1-2
groups consisting of hydrogen, C.sub.1 -C.sub.3 alkyl, hydroxy, or
C.sub.1 -C.sub.3 alkoxy;
A is CH.sub.2, O, NR.sup.25, C(.dbd.O), or S(O).sub.n ;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.t R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; --NR.sup.6 R.sup.7 ; aryl; --NR.sup.16
(CH.sub.2).sub.n NR.sup.6 R.sup.7 ; --(CH.sub.2).sub.k R.sup.25 ;
and (CH.sub.2).sub.t heteroaryl or (CH.sub.2).sub.t aryl, either of
which can optionally be substituted with 1-3 groups selected from
the group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl, C.sub.1
-C.sub.2 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.2 alkyl),
NH(C.sub.1 -C.sub.2 alkyl), N(C.sub.1 -C.sub.2 alkyl),, R.sup.9 is
hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and
C.sub.3 -C.sub.6 cycloalkyl substituted with 0-2 R.sup.18 ;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl,
(CH.sub.2).sub.t R.sup.22, and aryl substituted with 0-2 R.sup.18
;
R.sup.16 is independently selected at each occurrence from the
group consisting of hydrogen and C.sub.1 -C.sub.2 alkyl;
R.sup.17 is independently selected at each occurrence from the
group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl, C.sub.1
-C.sub.2 alkoxy, halo, and NR.sup.23 R.sup.24 ;
R.sup.18 is independently selected at each occurrence from the
group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl, C.sub.1
-C.sub.2 alkoxy, halo, and NR.sup.23 R.sup.24 ;
R.sup.22 is independently selected at each occurrence from the
group consisting of OR.sup.24, SR.sup.24, R.sup.23 R.sup.24, and
--C(.dbd.O)R.sup.25 ;
R.sup.23 and R.sup.24 are independently selected at each occurrence
from hydrogen and C.sub.1 -C.sub.2 alkyl;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,
4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl, chromanyl,
chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl,
indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,
isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
quinoxalinyl, quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl,
tetrazolyl, thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
R.sup.25a is independently selected at each occurrence from the
group consisting of H and C.sub.1 -C.sub.4 alkyl;
R.sup.29 is taken together with R.sup.4 to form a five membered
ring and is --C(R.sup.30).dbd.;
R.sup.30 is hydrogen, cyano, C.sub.1 -C.sub.2 alkyl, or
halogen;
k is 1-3;
p is 0-2;
q and r are 2; and
t and w are independently selected at each occurrence from 1-2.
More preferred compounds of this invention are those compounds of
Formula I wherein, when Y is CR.sup.3a or N:
R.sup.1 is independently selected at each occurrence from the group
consisting of C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2 haloalkyl,
NR.sup.6 R.sup.7, and OR.sup.8 ;
R.sup.3 is independently selected at each occurrence from the group
consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.2 haloalkyl,
NR.sup.6 R.sup.7, OR.sup.8, C(.dbd.O)R.sup.9, C(.dbd.O)NR.sup.6
R.sup.7, (CH.sub.2).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k
OR.sup.8, --C(CN)(R.sup.25)(R.sup.16) provided that R.sup.25 is not
an --NH-- containing ring, --C(OH)(R.sup.25)(R.sup.25a),
--(CH.sub.2).sub.p S(O).sub.n -alkyl, --C(.dbd.O)R.sup.25,
--CH(CO.sub.2 R.sup.16).sub.2, 2-pyridinyl, indolinyl, indolyl,
pyrazoyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
1H-indazolyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl,
4H-quinolizinyl, benzofuranyl, carbazolyl, chromenyl, cinnolinyl,
decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl,
indolizinyl, indolyl, isobenzofuranyl, isoindolinyl, isoindolyl,
isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl,
oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl pyrrolyl, quinazolinyl, quinolinyl,
quinoxalinyl, quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,
thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
R.sup.1a, R.sup.2, and R.sup.3a are independently selected at each
occurrence from the group consisting of hydrogen, methyl, and
cyano;
X is Cl, Br, I, OR.sup.8, NR.sup.14 R.sup.15, (CH.sub.2).sub.m
OR.sup.16, or (CHR.sup.16)NR.sup.14 R.sup.15 ;
X' is hydrogen, Cl, Br, I, OR.sup.8, NR.sup.14 R.sup.15,
(CH.sub.2).sub.m OR.sup.16, or (CHR.sup.16)NR.sup.14 R.sup.15 ;
R.sup.5 is halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3
haloalkyl, C.sub.1 -C.sub.6 alkoxy, (CHR.sup.16).sub.p OR.sup.8,
(CHR.sup.16).sub.p NR.sup.14 R.sup.15, or C.sub.3 -C.sub.6
cycloalkyl;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of
C.sub.1 -C.sub.6 alkyl, (CHR.sup.16).sub.p OR.sup.8, C.sub.1
-C.sub.6 alkoxy, and --(CH.sub.2).sub.k R.sup.13, or can be taken
together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --,
optionally substituted with --CH.sub.2 OCH.sub.3 ;
A is CH.sub.2, O, S(O).sub.n, N(C(.dbd.O)R.sup.17), N(R.sup.19),
C(H)(OR.sup.20), NR.sup.25, or C(.dbd.O);
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6
cycloalkyl, (CH.sub.2).sub.t R.sup.22, --NR.sup.6 R.sup.7,
--NR.sup.16 (CH.sub.2).sub.n NR.sup.6 R.sup.7, and
--(CH.sub.2).sub.k R.sup.25,
R.sup.9 is C.sub.1 -C.sub.4 alkyl;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl,
C.sub.3 -C.sub.6 cycloalkyl, and C.sub.4 -C.sub.6
cycloalkyl-alkyl;
R.sup.16 is hydrogen;
R.sup.1a is C.sub.1 -C.sub.3 alkyl;
R.sup.20 is independently selected at each occurrence from the
group consisting of hydrogen, C.sub.1 -C.sub.2 alkyl, and C.sub.2
-C.sub.3 alkenyl;
R.sup.22 is independently selected at each occurrence from the
group consisting of OR.sup.24, --S(O).sub.n R.sup.19, and
--C(.dbd.O)R.sup.25 ;
R.sup.23 and R.sup.24 are independently selected at each occurrence
from hydrogen and C.sub.1 -C.sub.2 alkyl;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,
4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, azocinyl, cinnolinyl, decahydroquinolinyl,
furazanyl, indolinyl, indolizinyl, indolyl, isoindolinyl,
isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
quinoxalinyl. quinuclidinyl, tetrahydrofuranyl, tetrazolyl,
thiazolyl, triazinyl; and 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
R.sup.25a, which can be optionally substituted with 0-3 R.sup.17,
is independently selected at each occurrence from the group
consisting of H, phenyl, pyrazolyl, imidazolyl,
2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl,
2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, azocinyl,
cinnolinyl, decahydroquinolinyl, furazanyl, indolinyl, indolizinyl,
indolyl, isobenzofuranyl, isoindolinyl, isoindolyl, isoquinolinyl,
benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,
piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyridazinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, .beta.-carbolinyl,
tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and
1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which
can be substituted with 0-3 groups chosen from keto and C.sub.1
-C.sub.4 alkyl;
k is 1-3;
p and q are 0-2; and
r is 1-2.
Other more preferred compounds of this invention are those
compounds of Formula I wherein, when Y is CR.sup.29 :
R.sup.1 is methyl;
R.sup.3 is C.sub.1 -C.sub.2 alkyl, NR.sup.6 R.sup.7, OR.sup.8,
SR.sup.8, C.sub.1 -C.sub.2 alkyl or aryl substituted with R.sup.27,
halogen, or is N-linked piperidinyl, piperazinyl, morpholino,
thiomorpholino, imidazolyl, or is 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, where substitution by R.sup.27 can occur on any carbon
containing substituent;
X is Br, I, S(O).sub.n R.sup.8, OR.sup.8, NR.sup.14 R.sup.15, or
alkyl substituted with R.sup.5 ;
X' is hydrogen, Br, I, S(O).sub.n R.sup.8, OR.sup.8, NR.sup.14
R.sup.15, or alkyl substituted with R.sup.5 ;
R.sup.5 is halogen, C.sub.1 -C.sub.2 alkyl, C.sub.1 -C.sub.2
alkoxy, or --NR.sup.14 R.sup.15 ;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen and C.sub.1 -C.sub.2 alkyl,
or, when considered with the commonly attached nitrogen, can be
taken together to form piperidine, piperazine, morpholine or
thiomorpholine;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen, C.sub.1 -C.sub.2 alkyl, and aryl optionally
substituted with 1-2 groups selected from hydrogen, C.sub.1
-C.sub.2 alkyl, C.sub.1 -C.sub.2 alkoxy, NHC(.dbd.O)(C.sub.1
-C.sub.2 alkyl), NH(C.sub.1 -C.sub.2 alkyl), and N(C.sub.1 -C.sub.2
alkyl).sub.2 ;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen and C.sub.1 -C.sub.2 alkyl;
and
R.sup.30 is hydrogen or cyano.
The following compounds are specifically preferred:
N-(2,4-dimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-methylphenyl)-N-methyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimid
inamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4-morpholino-6-methyl-2-pyrimid
inamine;
N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-cyclohexylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methy
l-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-py
rimidinamine;
N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidi
namine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyri
midinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiomorpholino-6-methyl-2-pyri
midinamine;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrmidinami
ne;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidina
mine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl
-2-pyrimidinamine;
N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamin
e;
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidi
namine;
N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl
-4-methyl-6-thiomorpholino-2-pyrimidinamine;
N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,4-diiodophenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxye
thylamino)-2-pyrimidinamine;
N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-iodophenyl)-N-methyl-4,6-diethyl-2-pyrmidinamine;
N-(2-iodophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;
4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-methylamino)pyridine;
4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)pyridine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;
2,6-dimethyl-4-(N-(2-bromo-4-(1-methylethyl)phenyl)amino)pyridine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylcarbon
yl)-2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(morpholinylmethyl)-
2-pyrimidinamine;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbon
yl)-2-pyrimidinamine;
Methyl-2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidin
ecarboxylate;
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyr
imidinecarboxamide;
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazi
nylcarbonyl)-2-pyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-1,3,5-triazin-2-am
ine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,
5-triazin-2-amine;
N-ethyl)-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-thiomorpholinyl)-
1,3,5-triazin-2-amine;
N-ethyl-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-morpholinyl)-1,3,5
-triazin-2-amine;
N-ethyl-N-{2
-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(1-piperidinyl)-1,3,5-triazin-2-
amine;
1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4-phenyl-6-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-phenyl-6-methyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-1)-3-cyano-4,6-dimethyl-7-azaindole:
1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-diethylamino-6-methyl-1,3,
5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dichloro-1,3,5
triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dimethoxy-1,3,5
triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-imidazolino-6-methyl-1,3,5
triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5
triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3,5
triazin-2-amine;
N-(2,4,6-trimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5
triazin-2-amine,
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3
,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-thiozolidino-6-methyl-1,3,5
triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-benzyloxy-6-methyl-1,3,5
triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-phenyloxy-6-methyl-1,3,5
triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(ethylpiperizinoate)}-6-methyl
-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(piperizinic
acid)}-6-methyl-1,3,5 triazin-2-amine;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-{3-(malon-2-yldiethyl
ester)}-6-methyl-1,3,5-triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-(1-cyano-1-phenylmethyl)-6-methyl
-1,3,5 triazin-2-amine;
N-(2-bromo-4,6-dimethoxyphenyl)-N-1-methylethyl-4-morpholino-6-methyl-1,3,5
triazin-2-amine;
N-(2-iodo-4-dimethylhydroxymethylphenyl)-N-ethyl-4,6-dichloro-1,3,5
triazin-2-amine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine, S-dioxide;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine, S-oxide;
N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-benzyloxy-1,3,5
triazin-2-amine;
N-(2-iodo-4-dimethylhydroxymethyl)-N-ethyl-4,6-dichloro-1,3,5
triazin-2-amine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-allyl-4-morpholino-6-methyl-2-pyrimidi
namine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-chloro-6-methyl-2-pyrimidinami
ne;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4(S)-(N-methyl-2-pyrrolidi
nomethoxy)-6-methyl-2-pyrimidinamine;
N-{2,6-dibromo-4-(1-methylethyl)phenyl}-4-thiomorpholino-6-methyl-2-pyrimid
inamine;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-{2-methylsulfinyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-thiazolidino-6-methyl-2-pyrimi
dinamine;
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4,6-dimethyl-2-pyrimidinamino)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-
benzothiazepine;
N-{2-methylsulfonyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-{2-ethylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinami
ne;
N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidin
amine;
N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrim
idinamine;
N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinam
ine;
N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{2-methylthio-4-(N-acetyl-N-methylamino)phenyl}-N-ethyl-4,6-dimethyl-2-py
rimidinamine;
N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyirmidinamine;
N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-{4-(1-methoxyethyl)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidina
mine;
N-{4-(N-methylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine;
N-{4-(N,N-dimethylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimid
inamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-formyl-6-methyl-2-pyrimidinam
ine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-hydroxyethoxymethyl-6-methyl-
2-pyrimidinamine;
N-(2-bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
;
N-(3-bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,3-dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2,6-dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano4-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-chloro-34yano-methyl-7-azaindole;
1-(2-bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole;
N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(3-bromo-5-methyl-pyridin-2-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;
N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5
triazin-2-amine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{N-(2-furylmethyl)-N-methylam
ino}carbonyl-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{(4,4-ethylenedioxypiperidino
)carbonyl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)carbonyl-6-m
ethylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)methyl-6-met
hylpyrimidinamine, hydrochloride salt;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(imidazol-1-yl)methyl-6-methy
lpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{3-(methoxyphenyl)methoxymeth
yl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-thiazolyl)carbonyl-6-methy
lpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-imidazolyl)carbonyl-6-meth
ylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(5-indolylcarbonyl)-6-methylp
yrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-fluorophenyl)carbonyl-6-me
thylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-carboxy-6-methylpyrimidinamin
e;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-acetyl-6-methylpyrimidinamine
;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-
methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{4-(methoxyphenyl)-3-pyridyl-
hydroxymethyl}-6-methylpyrimidinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimid
inamine, hydrochloride salt;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(1-aminoethyl)-6-methylpyrimi
dinamine;
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{2-(4-tetrazolyl)-1-methyleth
yl}-6-methylpyrimidinamine;
2-(N-{2-bromo-4-(2-propyl)phenyl}amino)-4-carbomethoxy-6-methylpyrimidine;
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-carbomethoxy-6-methylpyri
midine;
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-6-methylpyrimidine-4-morpho
linocarbonyl;
9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino purine;
9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-8-azapurine;
1{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-5,7-diaza-indazole;
and
2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-(morpholinomethyl)-6-meth
ylpyrimidine.
The above-described compounds and their corresponding salts possess
antagonistic activity for the corticotropin releasing factor
receptor and can be used for treating affective disorders, anxiety,
depression, irritable bowel syndrome, immune suppression,
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
drug and alcohol withdrawal symptoms, drug addiction, inflammatory
disorders, or fertility problems in mammals.
Further included in this invention is a method of treating
affective disorders, anxiety, depression, irritable bowel syndrome,
immune suppression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, drug and alcohol withdrawal symptoms, drug
addiction, inflammatory disorders, or fertility problems in mammals
in need of such treatment comprising administering to the mammal a
therapeutically effective amount of a compound of formula (I):
##STR16##
or a pharmaceutically acceptable salt or prodrug thereof, wherein Y
is CR.sup.3a,
N, or CR.sup.29 ;
when Y is CR.sup.3a or N:
R.sup.1 is independently selected at each occurrence from the group
consisting of C.sub.1 -C.sub.4 alkyl, halogen, C.sub.1 -C.sub.2
haloalkyl, NR.sup.6 R.sup.7, OR.sup.8, and S(O).sub.n R.sup.8 ;
R.sup.3 is C.sub.1 -C.sub.4 alkyl, aryl, C.sub.3 -C.sub.6
cycloalkyl, C.sub.1 -C.sub.2 haloalkyl, halogen, nitro, NR.sup.6
R.sup.7, OR.sup.8, S(O).sub.n R.sup.8, C(.dbd.O)R.sup.9,
C(.dbd.O)NR.sup.6 R.sup.7, C(.dbd.S)NR.sup.6 R.sup.7,
--(CHR.sup.16).sub.k NR.sup.6 R.sup.7, (CH.sub.2).sub.k OR.sup.8,
C(.dbd.O)NR.sup.10 CH(R.sup.11)CO.sub.2 R.sup.12,
--C(OH)(R.sup.25)(R.sup.25a), --(CH.sub.2).sub.p S(O).sub.n -alkyl,
--(CHR.sup.16)R.sup.25, --C(CN)(R.sup.25)(R.sup.16) provided that
R.sup.25 is not --NH-- containing rings, --C(.dbd.O)R.sup.25,
--CH(CO.sub.2 R.sup.16).sub.2, NR.sup.10
C(.dbd.O)CH(R.sup.11)NR.sup.10 R.sup.12, NR.sup.10
CH(R.sup.11)CO.sub.2 R.sup.12 ; substituted C.sub.1 -C.sub.4 alkyl,
substituted C.sub.2 -C.sub.4 alkenyl, substituted C.sub.2 -C.sub.4
alkynyl, substituted C.sub.1 -C.sub.4 alkoxy, aryl-(substituted
C.sub.1 -C.sub.4) alkyl, aryl-(substituted C.sub.1 -C.sub.4)
alkoxy, substituted C.sub.3 -C.sub.6 cycloalkyl, amino-(substituted
C.sub.1 -C.sub.4) alkyl, substituted C.sub.1 -C.sub.4 alkylamino,
where substitution by R.sup.27 can occur on any carbon containing
substituent; 2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl,
2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl,
phenyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl,
4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
azepinyl, benzofuranyl, benzothiophenyl, carbazolyl, chromanyl,
chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,
imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,
isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl
benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl,
.beta.-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl,
thiophenyl, triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or
2-tetrahydroisoquinolinyl either of which can be substituted with
0-3 groups chosen from keto and C.sub.1 -C.sub.4 alkyl;
J, K, and L are independently selected at each occurrence from the
group of
N, CH, and CX';
M is CR.sup.5 or N;
V is CR.sup.1a or N;
Z is CR.sup.2 or N;
R.sup.1a, R.sup.2, and R.sup.3a are independently selected at each
occurrence from the group consisting of hydrogen, halo, halomethyl,
C.sub.1 -C.sub.3 alkyl, and cyano;
R.sup.4 is (CH.sub.2).sub.m OR.sup.16, C.sub.1 -C.sub.4 alkyl,
allyl, propargyl, (CH.sub.2).sub.m R.sup.13, or --(CH.sub.2).sub.m
OC(O)R.sup.16 ;
X is halogen, S(O).sub.2 R.sup.8, SR.sup.8, halomethyl,
--(CH.sub.2).sub.p OR.sup.8, --OR.sup.8, cyano,
--(CHR.sup.16).sub.p NR.sup.14 R.sup.15, --C(.dbd.O)R.sup.8,
C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10
alkoxy, aryl-(C.sub.2 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is independently selected at each occurrence from the group
consisting of hydrogen, halogen, S(O).sub.n R.sup.8, halomethyl,
--(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p
NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1
-C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, and --C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)--C.sub.1 -.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl,
--(CHR.sup.16).sub.p OR.sup.8, --(CHR.sup.16).sub.p S(O).sub.n
R.sup.8, --(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3 -C.sub.6
cycloalkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl,
aryl-(C.sub.2 -C.sub.10)-akyl, aryl-(C.sub.1 -C.sub.10)-alkoxy,
cyano, C.sub.3 -C.sub.6 cycloalkoxy, nitro, amino-(C.sub.2
-C.sub.10)-alkyl, thio-(C.sub.2 -C.sub.10)-alkyl, SO.sub.n
(R.sup.8), C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or
--C(.dbd.O)NR.sup.14 R.sup.15, where substitution by R.sup.18 can
occur on any carbon containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, (C.sub.4
-C.sub.12)-cycloalkylalkyl, --(CH.sub.2).sub.k R.sup.13,
(CHR.sup.16).sub.p OR.sup.8, --(C.sub.1 -C.sub.6 alkyl)-aryl,
heteroaryl, aryl, --S(O).sub.n -aryl or --(C.sub.1 -C.sub.6
alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups are
optionally substituted with 1-3 groups selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
-C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro,
carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), cyano, and S(O).sub.z
--(C.sub.1 -C.sub.6 -alkyl); or can be taken together to form
--(CH.sub.2).sub.q A(CH.sub.2).sub.r --, optionally substituted
with 0-3 R.sup.17 ; or, when considered with the commonly attached
nitrogen, can be taken together to form a heterocycle, said
heterocycle being substituted on carbon with 1-3 groups consisting
of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, or C.sub.1 -C.sub.6
alkoxy;
A is CH.sub.2, O, NR.sup.25, C(.dbd.O), S(O).sub.n,
N(C(.dbd.O)R.sup.17), N(R.sup.19), C(H)(NR.sup.14 R.sup.15),
C(H)(OR.sup.20), C(H)(C(.dbd.O)R.sup.21), or N(S(O).sub.n
R.sup.21);
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen; C.sub.1 -C.sub.6 alkyl; --(C.sub.4
-C.sub.12) cycloalkylalkyl; (CH.sub.2).sub.n R.sup.22 ; C.sub.3
-C.sub.10 cycloalkyl; --NR.sup.6 R.sup.7 ; aryl; --NR.sup.16
(CH.sub.2).sub.n NR.sup.6 R.sup.7 ; --(CH.sub.2).sub.k R.sup.25 ;
and (CH.sub.2).sub.t heteroaryl or (CH.sub.2).sub.t aryl, either of
which can optionally be substituted with 1-3 groups selected from
the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6
alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6
alkyl).sub.2, nitro, carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl),
cyano, and S(O).sub.z (C.sub.1 -C.sub.6 -alkyl);
R.sup.9 is independently selected at each occurrence from R.sup.10,
hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.1 -C.sub.4 alkenyl, aryl substituted with 0-3 R.sup.18, and
--(C.sub.1 -C.sub.6 alkyl)-aryl substituted with 0-3 R.sup.18 ;
R.sup.10, R.sup.16, R.sup.23, and R.sup.24 are independently
selected at each occurrence from hydrogen or C.sub.1 -C.sub.4
alkyl;
R.sup.11 is C.sub.1 -C.sub.4 alkyl substituted with 0-3 groups
chosen from the following: keto, amino, sulfhydryl, hydroxyl,
guanidinyl, p-hydroxyphenyl, imidazolyl, phenyl, indolyl,
indolinyl, or, when taken together with an adjacent R.sup.10, are
(CH.sub.2).sub.t ;
R.sub.12 is hydrogen or an appropriate amine protecting group for
nitrogen or an appropriate carboxylic acid protecting group for
carboxyl;
R.sup.13 is independently selected at each occurrence from the
group consisting of CN, OR.sup.19, SR.sup.19, and C.sub.3 -C.sub.6
cycloalkyl;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.4 -C.sub.10
cycloalkyl-alkyl, and R.sup.19 ;
R.sup.17 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, NR.sup.23 R.sup.24, and (C.sub.1 -C.sub.6)
alkyl (C.sub.1 -C.sub.4) alkoxy;
R.sup.18 is independently selected at each occurrence from the
group consisting of R.sup.10, hydroxy, halogen, C.sub.1 -C.sub.2
haloalkyl, C.sub.1 -C.sub.4 alkoxy, C(.dbd.O)R.sup.24, and
cyano;
R.sup.19 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6
cycloalkyl, (CH.sub.2).sub.w R.sup.22, and aryl substituted with
0-3 R.sup.18 ;
R.sup.20 is independently selected at each occurrence from the
group consisting of R.sup.10, C(.dbd.O)R.sup.31, and C.sub.2
-C.sub.4 alkenyl;
R.sup.21 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4.sup.- alkoxy,
NR.sup.23 R.sup.24, and hydroxyl;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, OR.sup.24, SR.sup.24, NR.sup.23
R.sup.24, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl,
--S(O).sub.n R.sup.31, and --C(.dbd.O)R.sup.25 ;
R.sup.25, which can be optionally substituted with 0-3 R.sup.17, is
independently selected at each occurrence from the group consisting
of phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,
4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,
2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,
2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, 1H-indazolyl,
2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,
4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl,
benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,
isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl,
isoquinolinyl benzimidazolyl, isothiazolyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl,
oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,
pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
quinuclidinyl, .beta.-carbolinyl, tetrahydrofuranyl, tetrazolyl,
thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl; and
1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which
can be substituted with 0-3 groups chosen from keto and C.sub.1
-C.sub.4 alkyl;
R.sup.25a, which can be optionally substituted with 0-3 R.sup.17,
is independently selected at each occurrence from the group
consisting of H and R.sup.25 ;
R.sup.27 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.4
alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.2 -C.sub.4 alkoxy, aryl,
nitro, cyano, halogen, aryloxy, and heterocycle optionally linked
through O;
R.sup.31 is independently selected at each occurrence from the
group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7
cycloalkyl, C.sub.4 -C.sub.10 cycloalkyl-alkyl, and aryl-(C.sub.1
-C.sub.4) alkyl;
k, m, and r are independently selected at each occurrence from
1-4;
n is independently selected at each occurrence from 0-2;
p, q, and z are independently selected at each occurrence from
0-3;
t and w are independently selected at each occurrence from 1-6,
provided that when J is CX' and K and L are both CH, and M is
CR.sup.5, then
(A) when V and Y are N and Z is CH and R.sup.1 and R.sup.3 are
methyl,
(1) and R.sup.4 is methyl, then
(a) R.sup.5 can not be methyl when X is OH and X' is H;
(b) R.sup.5 can not be --NHCH.sub.3 or --N(CH.sub.3).sub.2 when X
and X' are --OCH.sub.3 ; and
(c) R.sup.5 can not be -N(CH.sub.3).sub.2 when X and X' are
--OCH.sub.2 CH.sub.3 ;
(2) and R.sup.4 is ethyl, then
(a) then R.sup.5 can not be methylamine when X and X' are
--OCH.sub.3 ;
(b) R.sup.5 can not be OH when X is Br and X' is OH; and
(c) R.sup.5 can not be --CH.sub.2 OH or --CH.sub.2
N(CH.sub.3).sub.2 when X is --SCH3 and X' is H;
(B) when V and Y are N, Z is CH, R.sup.4 is ethyl, R.sup.5 is
iso-propyl, X is Br, X' is H, and
(1) R.sup.1 is CH.sub.3, then
(a) R.sup.3 can not be OH, piperazin-1-yl, --CH.sub.2
-piperidin-1-yl, --CH.sub.2 -(N-4-methylpiperazin- 1-yl),
--C(O)NH-phenyl, --CO.sub.2 H, --CH.sub.2 O-(4-pyridyl),
--C(O)NH.sub.2, 2-indolyl, --CH.sub.2 O-(4-carboxyphenyl),
--N(CH.sub.2 CH.sub.3)(2-bromo-4-isopropylphenyl);
(2) R.sup.1 is --CH.sub.2 CH.sub.2 CH.sub.3 then R.sup.3 can not be
--CH.sub.2 CH.sub.2 CH.sub.3 ;
(C) when V, Y and Z are N, R.sup.4 is ethyl, and
(1) R.sup.5 is iso-propyl, X is bromo, and X' is H, then
(a) R.sup.3 can not be OH or --OCH.sub.2 CN when R.sup.1 is
CH.sub.3 ; and
(b) R.sup.3 can not be --N(CH.sub.3).sub.2 when R.sup.1 is
--N(CH.sub.3).sub.2 ;
(2) R.sup.5 is --OCH--, X is --OCH.sub.3, and X' is H, then R.sup.3
and R.sup.1 can not both be chloro;
further provided that when J, K, and L are all CH and M is
CR.sup.5, then
(D) at least one of V, Y, and Z must be N;
(E) when V is CR.sup.1a, Z and Y can not both be N;
(F) when Y is CR.sup.3a, Z and V can not both be N;
(G) when Z is CR.sup.2, V and Y must both be N;
(H) Z can be N only when both V and Y are N or when V is CR.sup.1a
and Y is CR.sup.3a ;
(I) when V and Y are N, Z is CR.sup.2, and R.sup.2 is H or C.sub.1
-C.sub.3 alkyl, and R.sup.4 is C.sub.1 -C.sub.3 alkyl, R.sup.3 can
not be 2-pyridinyl, indolyl, indolinyl, imidazolyl, 3-pyridinyl,
4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, furanyl,
5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;
(J) when V and Y are N; Z is CR.sup.2 ; R.sup.2 is H or C.sub.1
-C.sub.3 alkyl; R.sup.4 is C.sub.1 -C.sub.4 alkyl; R.sup.5, X,
and/or X' are OH, halo, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1
-C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, cyano, amino,
carbamoyl, or C.sub.1 -C.sub.4 alkanoyl; and R.sup.1 is C.sub.1
-C.sub.4 alkyl, then R.sup.3 can not be --NH(substituted phenyl) or
--N(C.sub.1 -C.sub.4 alkyl)(substituted phenyl);
and wherein, when Y is CR.sup.29 :
J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R.sup.3, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.16, R.sup.18, R.sup.19,
R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.27 are as defined
above and R.sup.25a, in addition to being as defined above, can
also be C.sub.1 -C.sub.4 alkyl, but
V is N;
R.sup.1 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl,
C.sub.2 -C.sub.4 alkynyl, C.sub.2 -C.sub.4 alkoxy, halogen, amino,
methylamino, dimethylamino, aminomethyl, or
N-methylaminomethyl;
R.sup.2 is independently selected at each occurrence from the group
consisting of hydrogen, halo, C.sub.1 -C.sub.3 alkyl, nitro, amino,
and --CO.sub.2 R.sup.10 ;
R.sup.4 is taken together with R.sup.29 to form a 5-membered ring
and is --C(R.sup.28).dbd. or --N.dbd. when R.sup.29 is
--C(R.sup.30).dbd. or --N.dbd., or --CH(R.sup.28)-- when R.sup.29
is
X is Cl, Br, I, S(O).sub.n R.sup.8, OR.sup.8, halomethyl,
--(CHR.sup.16).sub.p OR.sup.8, cyano, --(CHR.sup.16).sub.p
NR.sup.14 R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1
-C.sub.10 alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.1 -C.sub.10 )-alkoxy, nitro, thio-(C.sub.1
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)--C.sub.1 -C.sub.4 -alkyl,
-C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.14 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
X' is hydrogen, Cl, Br, I, S(O).sub.n R.sup.8, --(CHR.sup.16).sub.p
OR.sup.8, halomethyl, cyano, --(CHR.sup.16).sub.p NR.sup.14
R.sup.15, C(.dbd.O)R.sup.8, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.1 -C.sub.10,
alkoxy, aryl-(C.sub.1 -C.sub.10)-alkyl, C.sub.3 -C.sub.6
cycloalkyl, aryl-(C.sub.2 -C.sub.10)-alkoxy, nitro, thio-(C.sub.2
-C.sub.10)-alkyl, --C(.dbd.NOR.sup.16)-C.sub.1 -C.sub.4 -alkyl,
--C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8 R.sup.15 where
substitution by R.sup.18 can occur on any carbon containing
substituents;
R.sup.5 is halo, --C(.dbd.NOR.sup.16)-C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.6 alkyl, C1-C3 haloalkyl, C.sub.1 -C.sub.6 alkoxy,
(CHR.sup.16).sub.p OR.sup.8, (CHR.sup.16).sub.p S(O).sub.n R.sup.8,
(CHR.sup.16).sub.p NR.sup.14 R.sup.15, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.1 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, aryl-(C.sub.2
-C.sub.10)-alkyl, aryl-(C.sub.1 -C.sub.10)-alkoxy, cyano, C.sub.3
-C.sub.6 cycloalkoxy, nitro, amino-(C.sub.1 -C.sub.10)-alkyl,
thio-(C.sub.1 -C.sub.10)-alkyl, SO.sub.n (R.sup.8),
C(.dbd.O)R.sup.8, --C(.dbd.NOR.sup.16)H, or C(.dbd.O)NR.sup.8
R.sup.15 where substitution by R.sup.18 can occur on any carbon
containing substituents;
R.sup.6 and R.sup.7 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.k R.sup.13, (C.sub.4
-C.sub.12)-cycloalkylalkyl, C.sub.1 -C.sub.6 alkoxy, --(C.sub.1
-C.sub.6 alkyl)-aryl, heteroaryl, aryl, --S(O).sub.z -aryl or
--(C.sub.1 -C.sub.6 alkyl)-heteroaryl or aryl wherein the aryl or
heteroaryl groups are optionally substituted with 1-3 groups
selected from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
-C.sub.6 alkoxy, amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl),
NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl), nitro,
carboxy, CO.sub.2 (C.sub.1 -C.sub.6 alkyl), and cyano; or can be
taken together to form --(CH.sub.2).sub.q A(CH.sub.2).sub.r --,
optionally substituted with 0-3 R.sup.17 ; or, when considered with
the commonly attached nitrogen, can be taken together to form a
heterocycle, said heterocycle being substituted on carbon with 1-3
groups consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, or
C.sub.1 -C.sub.6 alkoxy;
R.sup.8 is independently selected at each occurrence from the group
consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, --(C.sub.4
-C.sub.12) cycloalkylalkyl, (CH.sub.2).sub.t R.sup.22, C.sub.3
-C.sub.10 cycloalkyl, --(C.sub.1 -C.sub.6 alkyl)-aryl, heteroaryl,
--NR.sup.16, --N(CH.sub.2).sub.n NR.sup.6 R.sup.7 ;
--(CH.sub.2).sub.k R.sup.25, --(C.sub.1 -C.sub.6 alkyl)-heteroaryl
or aryl optionally substituted with 1-3 groups selected from
hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
amino, NHC(.dbd.O)(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6
alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, nitro, carboxy, CO.sub.2
(C.sub.1 -C.sub.6 alkyl), and cyano;
R.sup.9 is independently selected at each occurrence from R.sub.2,
hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkyl,
C.sub.2 -C.sub.4 alkenyl, and aryl substituted with 0-3 R.sup.18
;
R.sup.14 and R.sup.15 are independently selected at each occurrence
from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl,
C.sub.3 -C.sub.6 cycloalkyl, (CH.sub.2).sub.t R.sup.22, and aryl
substituted with 0-3 R.sup.18 ;
R.sup.17 is independently selected at each occurrence from the
group consisting of R.sup.10, C.sub.1 -C.sub.4 alkoxy, halo,
OR.sup.23, SR.sup.23, and NR.sup.23 R.sup.24 ;
R.sup.20 is independently selected at each occurrence from the
group consisting of R.sup.10 and C(.dbd.O)R.sup.31 ;
R.sup.22 is independently selected at each occurrence from the
group consisting of cyano, R.sup.24, SR.sup.24, NR.sup.23 R.sup.24,
C.sub.3 -C.sub.6 cycloalkyl, --S(O).sub.n R.sup.31, and
--C(.dbd.O)R.sup.25 ;
R.sup.26 is hydrogen or halogen:
R.sup.28 is C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.4 alkenyl,
C.sub.2 -C.sub.4 alkynyl, hydrogen, C.sub.1 -C.sub.2 alkoxy,
halogen, or C.sub.2 -C.sub.4 alkylamino; R.sup.29 is taken together
with R.sup.4 to form a five membered ring and is: --CH(R.sup.30)--
when R.sup.4 is --CH(R.sup.28)--, --C(R.sup.30).dbd. or --N.dbd.
when R.sup.4 is --C(R.sup.28).dbd. or --N.dbd.;
R.sup.30 is hydrogen, cyano, C.sub.1 -C.sub.2 alkyl, C.sub.1
-C.sub.2 alkoxy, halogen, C.sub.1 -C.sub.2 alkenyl, nitro, amido,
carboxy, or amino;
R.sup.31 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, or
aryl-(C.sub.1 -C.sub.4) alkyl;
provided that when J, K, and L are all CH, M is CR.sup.5, Z is CH,
R.sup.3 is CH.sub.3,
R.sup.28 is H, R.sup.5 is iso-propyl, X is Br, X' is H, and R.sup.1
is CH.sub.3, then R.sup.30 can not be H, --CO.sub.2 H, or
--CH.sub.2 NH.sub.2 ;
and further provided that when J, K and L are all CH; M is CR.sup.5
; Z is N; and
(A) R.sup.29 is --C(R.sup.1).dbd.; then one of R.sup.28 or R.sup.30
is hydrogen;
(B) R.sup.29 is N; then R.sup.3 is not halo, NH.sub.2, NO.sub.2,
CF.sub.3, CO.sub.2 H, CO.sub.2 -alkyl, alkyl, acyl, alkoxy, OH, or
--(CH.sub.2).sub.m Oalkyl;
(C) R.sup.29 is N; then R.sup.28 is not methyl if X or X' are bromo
or methyl and R.sup.5 is nitro; or
(D) R.sup.29 is N, and R.sup.1 is CH.sub.3 and R.sup.3 is amino;
then R.sup.5 is not halogen or methyl.
Further included in this invention are pharmaceutical compositions
comprising a pharmaceutically acceptable carrier and
therapeutically effective amount of any one of the above-described
compounds.
The compounds provided by this invention (and especially labelled
compounds of this invention) are also useful as standards and
reagents in determining the ability of a potential pharmaceutical
to bind to the CRF receptor. These would be provided in commercial
kits comprising a compound provided by this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present invention it has been discovered that the provided
compounds useful as antagonists of Cortocotropin Releasing Factor
and for the treatment of effective disorders, anxiety, or
depression.
The present invention also provides methods for the treatment of
effective disorder, anxiety or depression by administering to a
host a therapeutically effective amount of a compound of formula
(I) as described above. By therapeutically effective amount is
meant an amount of a compound of the present invention effective to
antagonize abnormal levels of CRF or treat the symptoms of
affective disorder, anxiety or depression in a host.
The compounds herein described may have asymmetric centers. All
chiral, diastereomeric, and racemic forms are included in the
present invention. Many geometric isomers of olefins, C.dbd.N
double bonds, and the like can also be present in the compound
described herein, and all such stable isomers are comtemplated in
the present invention. It will be appreciated that certain
compounds of the present invention contain an asymmetrically
substituted carbon atom, and may be isolated in optically active or
racemic forms. It is well known in the art how to prepare optically
active forms, such as by resolution of racemic forms or by
synthesis, from optically active starting materials. Also, it is
realized that cis and trans geometric isomers of the compounds of
the present invention are described and may be isolated as a
mixture of isomers or as separated isomers forms. All chiral,
diastereomeric, and racemic forms and all geometric isomers forms
of a structure are intended, unless the specific stereochemistry or
isomer form is specifically indicated.
When any variable (for example, R.sup.1 through R.sup.10, m, n, A,
w, Z, etc.) occurs more than one time in any constituent or in
formula (I) or any other formula herein, its definition on each
occurrence is independent of its definition at every other
occurrence. Thus, for example, in --NR.sup.8 R.sup.9, each of the
substituents may be independently selected from the list of
possible R.sup.8 and R.sup.9 groups defined. Also, combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
As used herein, "alkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. "Alkenyl" is intended to include
hydrocarbon chains of either a straight or branched configuration
and one or more unsaturated carbon-carbon bonds which may occur at
any stable point along the chain, such as ethenyl, propenyl, and
the like. "Alkynyl" is intended to include hydrocarbon chains of
either a straight or branched configuration and one or more triple
carbon-carbon bonds which may occur at any stable point along the
chain, such as ethynyl, propynyl and the like. "Haloalkyl" is
intended to include both branched and straight-chain saturated
aliphatic hydrocarbon groups having the specified number of carbon
atoms, substituted with 1 or more halogens; "alkoxy" represents an
alkyl group of indicated number of carbon atoms attached through an
oxygen bridge; "cycloalkyl" is intended to include saturated ring
groups, including mono-, bi- or poly-cyclic ring systems, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo,
and iodo.
As used herein, "aryl" or "aromatic residue" is intended to mean
phenyl, biphenyl or naphthyl.
The term "heteroaryl" is meant to include unsubstituted,
monosubstituted or disubstituted 5-, 6- or 10-membered mono- or
bicyclic aromatic rings, which can optionally contain from 1 to 3
heteroatoms selected from the group consisting of O, N, and S and
are expected to be active. Included in the definition of the group
heteroaryl, but not limited thereto, are the following: 2-, or 3-,
or 4-pyridyl; 2- or 3-furyl; 2- or 3-benzofuranyl; 2-, or
3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or
4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1-
or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2- or
4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or
5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4-
or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2-
or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-
cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl
ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or
3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-,
or 4-isoquinolinyl.
As used herein, "carbocycle" or "carbocyclic residue" is intended
to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to
14-membered bicyclic or tricyclic or an up to 26-membered
polycyclic carbon ring, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocyles include, but
are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,
biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl
(tetralin).
As used herein, the term "heterocycle" is intended to mean a stable
5- to 7-membered monocyclic or bicyclic or 7- to 10-membered
bicyclic heterocyclic ring which is either saturated or
unsaturated, and which consists of carbon atoms and from 1 to 4
heteroatoms independently selected from the group consisting of N,
O and S and wherein the nitrogen and sulfur heteroatoms may
optionally be oxidized, and the nitrogen may optionally be
quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom which results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. Examples of
such heterocycles include, but are not limited to, pyridyl,
pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl,
quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl,
4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl,
6H- 1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl,
thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrole, imidazolyl,
pyrazolyl, isothiazolyl, isoxazole, pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolizinyl, isoindole, 3H-indolyl,
indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl,
quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,
piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,
morpholinyl or oxazolidinyl. Also included are fused ring and spiro
compounds containing, for example, the above heterocycles.
The term "substituted", as used herein, means that one or more
hydrogens of the designated moiety is replaced with a selection
from the indicated group, provided that no atom's normal valency is
exceeded, and that the substitution results in a stable compound.
When a substituent is keto (i.e., .dbd.O), then 2 hydrogens
attached to an atom of the moiety are replaced.
By "stable compound" or "stable structure" is meant herein a
compound that is sufficiently robust to survive isolation to a
useful degree of purity from a reaction mixture and formulation
into an efficacious therapeutic agent.
As used herein, the term "appropriate amino acid protecting group"
means any group known in the art of organic synthesis for the
protection of amine or carboxylic acid groups. Such amine
protecting groups include those listed in Greene and Wuts,
"Protective Groups in Organic Synthesis" John Wiley & Sons, New
York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol.
3, Academic Press, New York (1981), the disclosure of which is
hereby incorporated by reference. Any amine protecting group known
in the art can be used. Examples of amine protecting groups
include, but are not limited to, the following: 1) acyl types such
as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2)
aromatic carbamate types such as benzyloxycarbonyl (Cbz) and
substituted benzyloxycarbonyls,
1-(p-biphenyl)-1-methylethoxycarbonyl, and
9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types
such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl,
diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl
carbamate types such as cyclopentyloxycarbonyl and
adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and
benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol
containing types such as phenylthiocarbonyl and
dithiasuccinoyl.
The term "amino acid" as used herein means an organic compound
containing both a basic amino group and an acidic carboxyl group.
Included within this term are natural amino acids, modified and
unusual amino acids, as well as amino acids that are known to occur
biologically in free or combined form but usually do not occur in
proteins. Included within this term are modified and unusual amino
acids, such as, those disclosed in, for example, Roberts and
Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is
hereby incorporated by reference. Modified or unusual amino acids
that can be used in the practice of the invention include, but are
not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an
N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid,
homoarginine, norleucine, N-methylaminobutyric acid,
naphthylalanine, phenylglycine, .beta.-phenylproline, tert-leucine,
4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline,
N,N-dimethylaminoglycine, N-methylaminoglycine,
4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid,
trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and
4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid,
1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic
acid.
The term "amino acid residue" as used herein means that portion of
an amino acid (as defined herein) that is present in a peptide.
The term "peptide" as used herein means a compound that consists of
two or more amino acids (as defined herein) that are linked by
means of a peptide bond. The term "peptide" also includes compounds
containing both peptide and non-peptide components, such as
pseudopeptide or peptide mimetic residues or other non-amino acid
components. Such a compound containing both peptide and non-peptide
components may also be referred to as a "peptide analog".
The term "peptide bond" means a covalent amide linkage formed by
loss of a molecule of water between the carboxyl group of one amino
acid and the amino group of a second amino acid.
As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
of formula (I) is modified by making acid or base salts of the
compound of formula (I). Examples of pharmaceutically acceptable
salts include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like.
"Prodrugs" are considered to be any covalently bonded carriers that
release the active parent drug according to formula (I) in vivo
when such prodrug is administered to a mammalian subject. Prodrugs
of the compounds of formula (I) are prepared by modifying
functional groups present in the compounds in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compounds. Prodrugs include compounds of
formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded
to any group that, when administered to a mammalian subject,
cleaves to form a free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of prodrugs include, but are not limited to,
acetate, formate and benzoate derivatives of alcohol and amine
functional groups in the compounds of formula (I); and the
like.
Pharmaceutically acceptable salts of the compounds of the invention
can be prepared by reacting the free acid or base forms of these
compounds with a stoichiometric amount of the appropriate base or
acid in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol,
isopropanol, or acetonitrile are preferred. Lists of suitable salts
are found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, Pa. (1985), p. 1418, the disclosure of
which is hereby incorporated by reference.
SYNTHESIS
The novel substituted-2-pyridinamines, substituted triazines,
substituted pyridines and substituted anilines of the present
invention can be prepared by one of the general schemes outlined
below (Scheme 1-23).
Compounds of the Formula (I), wherein Z is CR.sup.2 and J is CX'
and K and L are both CH, can be prepared as shown in Scheme 1.
2-Hydroxy-4,6-dialkylpyrimidine (II) was converted to the
corresponding derivative (III) with an appropriate leaving group in
the 2-position such as, but not limited to, Cl, Br, SO.sub.2
CH.sub.3, OSO.sub.2 CH.sub.3, or OSO.sub.2 C.sub.6 H.sub.4
--CH.sub.3, or SCH.sub.3 by treatment with phosphorous oxychloride
(POCl.sub.3), phosphorous oxybromide (POBr.sub.3), methanesulfonyl
chloride (MsCl), p-toluenesulfonyl chloride (TsCl), or sodium
thiomethoxide optionally followed by oxidation with hydrogen
peroxide, chlorine gas, or an organic peracid, such as,
m-chloroperbenzoic ##STR17##
acid, respectively. This derivative was reacted with the
appropriate 2,4-substituted aniline (IV) in a high boiling solvent,
such as, but not limited to, ethylene glycol, methoxyethoxyethanol
etc., or in an aprotic solvent such as tetrahydrofuran, dioxane,
toluene, xylene, or N,N-dimethyformamide, facilitated by the
optional use of a base such as sodium hydride (NaH), lithium
diisopropylamide (LDA), which are preferred. The coupled product
(V) was treated with a base such as NaH or LDA in an aprotic
solvent such as tetrahydrofuran (THF) or N,N-dimethylformamide
(DMF) or in a combination of potassium tert-butoxide in t-butanol
(tBuOK/tBuOH) followed by an alkylating agent R.sup.4 L', such as
an alkyl iodide, mesylate or tosylate to afford the corresponding
alkylated product of Formula (I).
The compounds of Formula (I), wherein V and Y are N and Z, J, K,
and L are all CH, can be prepared as shown in Scheme 2. The
substituted aniline (VI) was converted to the corresponding
guanidinium salt (VII) by treatment with the appropriate reagent
such as cyanamide. ##STR18##
The guanidinium salt (VII) was reacted with a .beta.-diketone
(VIII) in the presence of a base such as potassium carbonate
(K.sub.2 CO.sub.3) in N,N-dimethylformamide (DMF) or in an
alcoholic solvent in the presence of the corresponding alkoxide to
afford the corresponding pyrimidine (IX). This was subsequently
alkylated to provide (X), a compound of Formula (I) wherein X' is
hydrogen, by conditions identical to those described in Scheme
1.
Compounds of the Formula (I), wherein V and Y are N and Z, J, K,
and L are all CH and R.sup.3 is NR.sup.6 R.sup.7, can be prepared
as shown in Scheme 3. Treatment of 2,4-dichloro-6-alkylpyrimidine
(XI) with a primary or secondary amine in the presence of a
non-nucleophilic base such as a trialkylamine afforded selectively
the corresponding 4-substituted amino adduct (XII). ##STR19##
This in turn, was reacted with the substituted aniline (IV) under
conditions identical to those described in Scheme 1 to afford the
corresponding secondary pyrimidinamine (XIII). This was alkylated
under conditions described in Schemes 1 and 2. ##STR20##
Compounds of Formula (I) wherein J, K, and L are CH and Z is
CR.sup.2 and V and Y are N can also be prepared by the route
outlined in Scheme 4. The guanidinium salt (XII) was reacted with a
.beta.-ketoester (XV) in the presence of a base such as an alkoxide
in the corresponding alcoholic solvent to give the adduct (XVI).
Treatment of the hydroxy group in (XVI) with either phosphorous
oxychloride, phosphorous oxybromide, methanesulfonyl chloride,
p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride
provided (XVII), wherein the L is a leaving group and is,
respectively, Cl, Br, I, OMs, OTs, or OTf. The L group of (XVII)
was displaced with a nucleophile such as NR.sup.6 R.sup.7,
OR.sup.6, SR.sup.6, CN, an organolithium, organomagnesium,
organosodium, organopotassium, an alkyl cuprate, or in general an
organometallic reagent to the corresponding adduct (IX), which was
further alkylated under the standard conditions to produce
(XVIII).
Compounds of the Formula (I) that are substituted at the 2-position
of the phenyl ring could be prepared as outlined in Scheme 5.
##STR21##
Compounds of the Formula (I) wherein X is other than bromine can be
prepared by the intermediates shown in Scheme 5. Reaction of the
2-halo compound (V) wherein X is bromine or hydrogen with a
metalating agent such as, but not limited to, n-BuLi or t-BuLi in
an aprotic solvent, preferably ether or tetrahydrofuran, provided
the corresponding 2-lithio intermediate (X=Li, not isolated) which
was further reacted with an electrophile such as iodine or
trimethyltin chloride ((CH.sub.3).sub.3 SnCl) to give the
corresponding 2-substituted product (XIX). These intermediates can
also be further reacted using palladium-catalyzed coupling
reactions well known to one of skill in the art to prepare the
compounds of the invention.
Compounds of the Formula (I) wherein Z, K and L are all CHI, J is N
or CH, and R' is ethyl can be prepared as illustrated in Scheme 6.
Sequential addition/re-oxidation of an alkyllithium to
2-chloropyrimidine can provide intermediate (XXII) wherein the
R.sup.1 and R.sup.3 can be independent of one another. Displacement
of the chlorine by a suitable nitrogen nucleophile such as an
aniline under similar conditions of Scheme 1, followed by
attachment of the R.sup.4 group by alkylation in an analogous
method of Schemes 1 or 2 can provide the compounds of the
invention. ##STR22##
Compounds of the Formula (I) wherein Z is N can be prepared
according to the method outlined in Scheme 7. Known triazine
(XXIII), synthesis of which is reported in J. Amer. Chem. Soc.
77:2447 (1956), can be reacted with a substituted aniline (IV) in a
analogous manner to Scheme 1. Similarly, the 2,4 dichloro
6-methyltriazine, which can be prepared via the method reported in
U.S. Pat. No. 3,947,374 can be coupled to the substituted aniline
(IV) to provide (XXIV) where R.sup.3 is chlorine. Nucleophilic
addition in protic or aprotic solvents allows for a variety of
substituents at this position (XXV). Alkylation of the secondary
amine as previously described provide triazine compounds of formula
(I). ##STR23##
Compounds wherein R.sup.3 is carboxy-derived are synthesized
according to Scheme 8. A pyrimidine ester of formula (XXVI), which
is prepared by the literature method reported in Budesinsky and
Roubinek, Collection. Czech. Chem. Comm. 26:2871-2885 (1961) is
reacted with an amine of formula (IV) in the presence of an inert
solvent to afford an intermediate of formula (XXVII). Inert
solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl
ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons
(preferably dioxane), dialkylformamides (preferably
N,N-dimethylformamide), dialkylacetamides, (preferably
N,N-dimethylacetamide), cyclic amides, (preferably
N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl
sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic
hydrocarbons of 6 to carbons. Compounds of formula (XXVII) are
treated with a base and a compound of Formula R.sup.4 X, where X is
halogen (preferably Cl, Br or I) in an inert solvent. Such bases
include a tertiary amine, an alkali metal hydride ##STR24##
(preferably sodium hydride), an aromatic amine (preferably
pyridine), or an alkali metal carbonate or alkoxide. The choice of
inert solvent must be compatible with the choice of base (see J.
March, Advanced Organic Chemistry (New York: J. Wiley and Sons,
1985) pp. 364-366, 412; H. O. House, Modern Synthetic Reactions
(New York: W. A. Benjamin Inc., 1972, pp. 510-536)). Solvents
include lower alkyl alcohols of 1 to 6 carbons, lower
alkanenitriles (preferably acetonitrile), dialkyl ethers of 4 to 10
carbons, cyclic ethers of 4 to 10 carbons (preferably
tetrahydrofuran or dioxane), dialkylformamides (preferably
N,N-dimethylformamide), cyclic amides, (preferably
N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl
sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic
hydrocarbons to 6 to 10 carbons. Esters of formula (XXVIII) may be
converted to acids of formula (XXIX) by acidic or basic hydrolysis
(cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and
Sons, 1985) pp. 334-338) or by treatment with an alkali metal salt
(preferably LiI or NaCN) in the presence of an inert solvent at
temperatures ranging from 50 to 200.degree. C. (preferably 100 to
180.degree. C.) (cf. McMurray, J. E. Organic Reactions, Dauben, W.
G. et al., eds., J. Wiley and Sons, New York (1976), Vol. 24, pp.
187-224). Inert solvents include dialkylformamides (preferably
N,N-dimethylformamide), dialkylacetamides, (preferably
N,N-dimethylacetamide), cyclic amides, (preferably
N-methylpyrrolidinone), and dialkyl sulfoxides (preferably dimethyl
sulfoxide), or aromatic amines (preferably pyridine). Acids of
formula (XXIX) may be treated with a halogenating agent to give an
acid halide, which may or may not be isolated, then reacted with an
amine of formula HNR.sup.6 R.sup.7, with or without an inert
solvent, with or without a base, as taught by the literature (J.
March, Advanced Organic Chemistry, J. Wiley and Sons, New York
(1985), pp. 370-373, 389), to provide amides of formula (XXX).
Halogenating agents include thionyl chloride (SOCl.sub.2), oxalyl
chloride ((COCl).sub.2), phosphorous trichloride (PCl.sub.3),
phosphorous pentachloride (PCl.sub.5), or phosphorous oxychloride
(POCl.sub.3). Inert solvents include lower halocarbons of 1 to 6
carbons and 2 to 6 halogens (preferably dichloromethane or
dichloroethane), dialkyl ethers of 4 to 10 carbons, cyclic ethers
of 4 to 10 carbons (preferably dioxane) or aromatic hydrocarbons to
6 to 10 carbons. Bases include trialkyl amines or aromatic amines
(preferably pyridine). Alternatively, esters of formula (XXVIII)
may be reacted with an amine of formula HNR.sup.6 R.sup.7, with or
without an inert solvent, with or without a base, as taught by the
literature (cf. J. March, Advanced Organic Chemistry (New York: J.
Wiley and Sons, 1985) pp. 370-373, 389) to generate amides of
formula (XXX). Solvents include lower alkyl alcohols of 1 to 6
carbons, lower alkanenitriles (preferably acetonitrile), dialkyl
ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons
(preferably tetrahydrofuran or dioxane), dialkylformamides
(preferably N,N-dimethylformamide), dialkylacetamides, (preferably
N,N-dimethylacetamide), cyclic amides, (preferably
N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl
sulfoxide), hydrocarbons of 5 to 10 carbons or aromatic
hydrocarbons to 6 to 10 carbons. Such bases include a tertiary
amine, an alkali metal hydride (preferably sodium hydride), an
aromatic amine (preferably pyridine), or an alkali metal carbonate
or alkoxide. Amides of formula (XXX) may be treated with a reducing
agent in an inert solvent to provide amines of formula (XXXI). Such
reducing agents include, but are not limited to, alkali metal
aluminum hydrides, preferably lithium aluminum hydride, alkali
metal borohydrides (preferably lithium borohydride), alkali metal
trialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminum
hydride), dialkylaluminum hydrides (such as di-isobutylaluminum
hydride), borane, dialkylboranes (such as di-isoamyl borane),
alkali metal trialkylboron hydrides (such as lithium triethylboron
hydride). Inert solvents include lower alkyl alcohols of 1 to 6
carbons, ethereal solvents (such as diethyl ether or
tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10
carbons. Reaction temperatures for the reduction range from about
-78.degree. to 200.degree. C., preferably about 50.degree. to
120.degree. C. The choice of reducing agent and solvent is known to
those skilled in the art as taught in the above cited March
reference (pp. 1093-1110).
Scheme 9 depicts the synthesis and chemical modifications to form
compounds of formula (XXXIII). Esters of formula (XXVIII) or acids
of formula (XXIX) may be treated with a reducing agent in an inert
solvent to provide alcohols of formula (XXXII). Such reducing
agents include, but are not limited to, alkali metal aluminum
hydrides, preferably lithium aluminum hydride, alkali metal
borohydrides (preferably lithium borohydride), alkali metal
trialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminum
hydride), dialkylaluminum hydrides (such as di-isobutylaluminum
hydride), borane, dialkylboranes (such as di-isoamyl borane),
alkali metal trialkylboron hydrides (such as lithium triethylboron
hydride). Inert solvents include lower alkyl alcohols of 1 to 6
carbons, ethereal solvents (such as diethyl ether or
tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10
carbons. Reaction temperatures for the reduction range from about
-78.degree. to 200.degree. C., preferably about 50.degree. to
120.degree. C. The choice of reducing agent and solvent is known to
those skilled in the art as taught in the above cited March
reference (pp. 1093-1110). Alcohols of Formula (XXXII) may be
converted to ethers of formula (XXXIII) by treatment with a base
and a compound of Formula R.sup.8 X, where X is halogen. Bases
which may be used for this reaction include, but are not limited
to, alkali metal hydrides, preferably sodium hydride, alkali metal
carbonates, preferably potassium carbonate, alkali metal
dialkylamides, preferably lithium di-isopropylamide, alkali metal
bis-(trialkylsilyl)amides, preferably sodium
bis-(trimethylsilyl)amide, alkyl alkali metal compounds (such as
butyl lithium), alkali metal alkoxides (such as sodium ethoxide),
alkyl alkaline earth metal halides (such as methyl magnesium
bromide), trialkylamines (such as triethylamine or
di-isopropylethylamine), polycyclic di-amines (such as 1,4
diazabicyclo[2.2.2]octane or 1,8-diazabicyclo-[5.4.0]undecene) or
quaternary ammonium salts (such as Triton B). The choice of inert
solvent must be compatible with the choice of base (J. March,
Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) pp.
255-446; H. O. House, Modern Synthetic Reactions (New York:
##STR25##
W. A. Benjamin Inc., 1972, pp. 546-553)). Solvents include lower
alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10
carbons, cyclic ethers of 4 to 10 carbons, preferably
tetrahydrofuran or dioxane, dialkylformamides, preferably
N,N-dimethylformamide, dialkylacetamides, preferably
N,N-dimethylacetamide, cyclic amides, preferably
N-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatic
hydrocarbons to 6 to 10 carbons.
Alternatively, compounds of formula (XXXII) may be converted to
compounds of formula (XXXIV), where Y is halide, arylsulfonyloxy
(preferably p-toluenesulfonyloxy), alkylsulfonyloxy (such as
methanesulfonyloxy), haloalkylsulfonyloxy (preferably
trifluoromethyl-sulfonyloxy), by reaction with a halogenating agent
or a sulfonylating agent. Examples of halogenating agents include,
but are not limited to, SOCl.sub.2, PCl.sub.3, PCl.sub.3,
POCl.sub.3, Ph.sub.3 P--CCl.sub.4, Ph.sub.3 P--CBr.sub.4, Ph.sub.3
P--Br.sub.2, Ph.sub.3 P--I.sub.2, PBr.sub.3, PBr.sub.5. The choice
of halogenating agents and reaction conditions are known to those
skilled in the prior art (March reference, pp. 382-384).
Sulfonylating agents include, but are not limited to, (lower
alkyl)sulfonyl chlorides (preferably methanesulfonyl chloride),
(lower haloalkyl) sulfonic anhydrides (preferably
trifluoromethylsulfonic anhydride, phenyl or alkyl
substituted-phenyl sulfonyl chlorides (preferably p-toluenesulfonyl
chloride). The sulfonylation or halogenations may require a base as
taught by the literature (March reference, pp. 1172, 382-384). Such
bases include a tertiary amine, an alkali metal hydride (preferably
sodium hydride), an aromatic amine (preferably pyridine), or an
alkali metal carbonate or alkoxide. Solvents for the halogenation
or sulfonylation should be inert under the reaction conditions as
taught by the literature. Such solvents include lower halocarbons
(preferably dichloromethane or dichloroethane), or ethereal
solvents (preferably tetrahydrofuran or dioxane). Intermediates of
formula (XXXIV) may then be converted to compounds of formula
(XXXIII) by treatment with a compound of formula R.sup.8 OH with or
without a base, in an inert solvent (March reference, pp. 342-343).
Such bases include alkali metal hydrides, preferably sodium
hydride, alkali metal carbonates, preferably potassium carbonate,
alkali metal dialkylamides, preferably lithium diiisopropylamide,
alkali metal bis-(trialkylsilyl)amides, preferably sodium
bis-(trimethylsilyl)amide, alkyl alkali metal compounds (such as
n-butyllithium), alkali metal alkoxides (such as sodium ethoxide),
alkyl alkaline earth metal halides (such as methyl magnesium
bromide), trialkylamines (such as triethylamine or
di-isopropylethylamine), polycyclic diamines (such as 1,4
diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undecene) or
quaternary ammonium salts (such as Triton B). Solvents include
lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10
carbons, cyclic ethers of 4 to 10 carbons, preferably
tetrahydrofuran or dioxane, dialkylformamides, preferably
N,N-dimethylformamide, dialkylacetamides, preferably
N,N-dimethylacetamide, cyclic amides, preferably
N-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatic
hydrocarbons to 6 to 10 carbons.
Intermediates of formula (XXXIII) may be prepared from
intermediates of formula (XXXII) by reaction with a
triarylphosphine (preferably triphenylphosphine), a di-(lower
alkyl) azodicarboxylate) and a compound of formula R.sup.8 OH in
the presence of an inert solvent as described in the general
literature (Mitsunobu, O., Synthesis 1:1-28 (1981)).
Compounds of formula (XXXI) may be prepared by treatment of a
compound of formula (XXXIV) with a compound of Formula HNR.sup.6
R.sup.7, with or without a base, in an inert solvent (Scheme 9).
Such bases and inert solvents may be the same ones used for the
transformation of compounds (XXVIII) to compounds (XXX) in Scheme
8.
Compounds of Formula (I) which are substituted at the 4-position of
the pyrimidine ring can be prepared as outlined in Scheme 10.
##STR26##
Known pyrimidine (XXXV), synthesis of which is reported in Eur. J.
Med. Chem. 23:60 (1988), can be reacted with a substituted aniline
(IV) in an analogous manner to Scheme 1. Treatment of the hydroxy
group in (XXXVI) with either phosphorous oxychloride, phosphorous
oxybromide, p-toluenesulfonyl chloride, or trifluoromethanesulfonic
anhydride provided (XXXVII), wherein the L is a leaving group.
Alkylation under the standard conditions gives (XXXVIII). The L
group of (XXXVIII) was displaced with a nucleophile such as
NR.sup.6 R.sup.7, OR.sup.6, SR.sup.6, CN, or an organometallic
reagent to the corresponding adduct (XXXIX).
Compounds of the Formula (I), wherein X or X' is alkylmercapto, or
functionalized alkylmercapto can be synthesized under the
conditions described in Scheme 11. ##STR27##
Treatment of the appropriately ortho-functionalized aniline XXXIX
with a substituted 2-mercaptopyrimidine XL in the presence of a
base such as potassium carbonate, sodium carbonate, alkali metal
alkoxide, potassium sodium or lithium hydride, a lithium, sodium or
potassium dialkylamide, or an alkali metal in the presence of
copper powder or copper salts gives the corresponding aryl sulfide
XLI which is subjected to a Smiles rearrangement by treatment with
an strong acid such as hydrochloric, hydrobromic, hydriodic,
sulfuric, phosphoric or perchloric, to give the corresponding
disulfide XLIII. This is reduced to the sulfide XLIV with a
reducing agent such as sodium borohydride and alkylated on the
sulfur with the appropriate alkylating agent such as an alkyl
halide, tosylate or mesylate. The rearrangement of XLI may be
carried out with a strong base such as lithium, sodium, or
potassium hydride; lithium, sodium, or potassium dialkylamide; or
lithium sodium or potassium metal, in an appropriate solvent such
as decahydronaphthalene, xylenes, high boiling alcohols,
dimethylformamide, dimethylsulfoxide, dimethylacetamide, and
N-methylpyrrolidinone. The rearrangement product can be selectively
alkylated on the sulfur with the use of a base such as potassium,
sodium or lithium carbonate, potassium, sodium or lithium alkoxide,
or trialkylamine and the appropriate alkylating agent as described
above. The alkylsulfide can be further alkylated on the nitrogen by
using identical conditions as described above to yield compound
XLV.
Compounds of formula (I), wherein R.sup.3 is (CH.sub.2).sub.k
OR.sup.8 and R.sup.8 is (CH.sub.2).sub.t C(.dbd.O)OR.sup.24,
(CH.sub.2),C(.dbd.O)NR.sup.6 R.sup.7, or (CH.sub.2).sub.t NR.sup.6
R.sup.7 can be made according to Scheme 12. ##STR28##
Compounds XLVII, XLVIII, and XLIX are made using the product of
Example 24 as starting material by procedures analogous to those
used to make the products of Examples 25, 16, and 17
respectively.
The novel 7-azaindoles of the present invention are prepared by
Scheme 13 outlined below. The potassium salt of
formylsuccinonitrile is treated with the appropriate substituted
aniline L to give LI. This undergoes base catalyzed cyclization to
a 1-aryl-2-amino-4-cyanopyrrole LII. Reaction with an appropriate
1,3-dicarbonyl compound gives the desired 7-azaindole LIII.
##STR29##
The nitrile substituent at position 3 of structure LIII is readily
removed by refluxing the 3-cyano compound with 65% sulfuric acid.
Position 3 then can be resubstituted by halogenation or nitration.
Reduction of the nitro group can provide the 3-amino
substituent.
Alternatively, the nitrile group can be converted to desired L
groups by methods described in "Comprehensive Organic
Transformations", by Richard C. Larock, VCH Publishers, Inc., New
York, N.Y., 1989. For instance, the nitrile group can be reduced
with diisobutylaluminum hydride to give the 3-aldehyde. The
3-aldehyde can be reduced via the hydrazone under Wolff-Kishner
conditions (KOH in hot diethylene glycol) to give L=methyl.
Furthermore, the aldehyde can be converted to L.dbd.CH.dbd.CH.sub.2
by adding it to a mixture of methyltriphenylphosphonium bromide and
potassium tertiary-butoxide in tetrahydrofuran (Wittig reaction).
Reduction of the ethenyl group to give L.dbd.CH.sub.2 CH.sub.3 can
be effected by hydroboration-protonolysis (J. Am. Chem. Soc.
81:4108(1959)).
Scheme 13 generally provides a mixture isomeric in substituents
R.sup.1 and R.sup.3, which then can be separated, Sometimes the
preferred isomer is the one obtained in lower yield. In that event
Scheme 14 can be used to prepare the preferred isomer. Intermediate
LII is treated with the appropriate acyl- or aroyl-acetic ester
under either thermal or acid-catalyzed conditions to give the
6-hydroxy compound LV. Compound LV is converted to the 6-chloro
compound LVI and de-cyanylated to compound LVII. When R.sup.1
substituents other than chloro are desired, the chloro group can be
converted to other substituents. For instance, treatment of
compound LVII with an alkyl Grignard reagent can provide compound
LVIII where R.sup.1 =alkyl. Heating with a primary or secondary
amine can provide compound LVIII where R.sup.1 =amino.
##STR30##
Scheme 15 affords another route to compounds of this invention.
Intermediate LII can be treated with the appropriate
acylacetaldehyde dialkyl acetal under acid catalyzed conditions to
give compounds LXa and LXb, 7-azaindoles unsubstituted at positions
4 and 6 respectively. Compound LXa can be oxidized with
m-chloroperoxybenzoic acid to give the N-oxide compound LXI.
Heating compound LXI with phosphorus oxychloride can give compound
XIIa, which can be decyanylated to compound LXIII.
Compound LXIV where R.sup.3 is an amino substituent can be prepared
by heating LXIII with the appropriate amine; where R.sup.3
=alkoxide, the metal alkoxide can be heated with LXIII; where
R.sup.3 =aryl, compound LXIII can treated with the arylboronic acid
in the presence of tetrakis(triphenylphosphine)p alladium (TTPP)
and sodium carbonate; and where R.sup.3 =alkyl, alkenyl, aralkyl,
and cycloalkyl, compound LXIII can be coupled with the appropriate
organotin reagent, also in the presence of 7TPP.
Compound LXIV where R.sup.3 is a nitro group can be prepared by
nitration of LXI, decyanylation, and reduction of the N-oxide with
a trivalent phosphorus compound such as triethyl phosphite.
Compound LXb can be substituted in the 6 position using methods
described for the substitution of LXa. ##STR31##
The novel 7-azabenzimidazoles of this invention can be prepared as
outlined in Scheme 16 where R.sup.29 is nitrogen. Compounds L and
LXV can react upon heating in the presence of a base, e.g. sodium
hydride, to give the diarylamine LXVI. Reduction of the nitro group
with stannous chloride can give LXVII, which can be closed to the
7-azabenzimidazole LXVIII. ##STR32##
The purines of this invention can be prepared as shown in Schemes
17 and 18.
Compounds L and LXIX (J. Heterocyclic Chem. 28:465 (1991)) can be
heated in the presence of a base, e.g. sodium hydride, to give
compound LXX. Heating LXX with the appropriate carboxylic acid in
the presence of a mineral acid catalyst can give LXXI where
R.sup.28 is hydrogen, alkyl, alkenyl, or alkynyl. The chloro
substituent can then be converted to R.sup.3 to give compounds
LXXII by using one of the methods described above for the
introduction of R.sup.3 to obtain compounds LXIV. ##STR33##
Scheme 18 can be used to prepare purines where R.sup.28 is halogen
or alkoxide. Compounds LXX can be heated with a dialkyl carbonate,
such as diethyl carbonate, to give the carbonyl compound LXXIII; if
the conversion is undesirably slow, more reactive species such as
trichloromethyl chlorocarbonate or carbonyl diumidazole can be used
in place of diethyl carbonate. The chloro substituent can then be
converted to R.sup.3 to give LXXIV by using one of the methods
described above for the introduction of R.sup.3 to obtain LXIV.
Heating LXXIV with phosphorus oxychloride can give the
2-chloropurine, LXXV. To prepare the 2-alkoxypurines, LXXVI, LXXV
can be heated with a metal salt of the alcohol R.sup.31 OH, e.g.
the sodium or potassium salt, wherein in R.sup.31 is C.sub.1
-C.sub.4 alkyl. ##STR34##
The method of synthesis of the 7-azaindolines of this invention is
shown in Scheme 19.
A number of compounds of the general structure LXXVIII with desired
R.sup.1 and R.sup.2 groups have been described by W. Paudler and
T.-K. Chen, J. Heterocyclic Chem. 7:767 (1970). These can be
oxidized with a peracid, e.g. m-chloroperoxybenzoic acid, to the
sulfone LXXIX. Sulfone LXXIX can be heated in the presence of the
desired aniline and a base, e.g. sodium hydride to give the diaryl
amine LXXX. Alkylation of LXXX with the desired unsubstituted or
4-substituted 3-butynyl iodide (or 3-butynol mesylate) can give
LXXXI. LXXXI can undergo an intramolecular Diels-Alder reaction to
give LXXXII.
In a number of cases, the desired 4-substituted 3-butynyl iodide is
not readily available or is unstable. In that event unsubstituted
3-butynyl iodide is used to give compound LXXXII where R.sup.3 =H.
##STR35##
The synthesis of the 5,7-diazaindoles of this invention is outlined
in Scheme 20.
The desired formamidine LXXXIII can be treated with LXXXIV in the
presence of sodium ethoxide in ethanol to give the pyrimidine
LXXXV. Refluxing LXXXV in phosphorus oxychloride gives the
dichloropyrimidine LXXXVI. Compound LXXXVI can be converted to the
carbonyl compound LXXXVII by treatment with one equivalent of ozone
at -78.degree. to give an ozonide, which on treatment with sodium
iodide and acetic acid gives the desired carbonyl compound. The
preparation of LXXXVII (R.sup.1 =H, R.sup.28 =CH.sub.3 and R.sup.1
=R.sup.28 =CH.sub.3) by a different route has been described by E.
Basagni et al., Bull. Soc. Chim. Fr., 4338 (1969).
Before the coupling reaction, the carbonyl of compound LXXXVII is
protected by treatment with 2,2-dimethoxypropane in the presence of
a catalytic amount of acid to give compound LXXXVIII. Compound
LXXXVIII is then coupled with the appropriate aniline L by heating
in the presence of a base, e.g. sodium hydride, to give compound
LXXXIX. Compound LXXXIX can be cyclized to give the 5,7-diazaindole
XC, the target compound wherein R.sup.3 =Cl. Compound XC is also a
useful intermediate for the preparation of Compounds XCI with other
R.sup.3 groups. For example, heating the chloro compound with the
appropriate amine gives the desired amino compound. Heating with a
metal alkoxide gives the desired alkoxy compound. Treating compound
XC (R.sup.3 =Cl) with R.sup.3 MgBr (R.sup.3 =alkyl, aryl, or
aralkyl) converts the chloro compound to the desired alkyl, aryl,
or aralkyl compound XCI. ##STR36## ##STR37##
Compounds wherein R.sup.5 is dimethylhydroxymethyl, X' is iodine
and R.sup.1 and R.sup.3 are chlorine can be prepared according to
scheme 21. Ethyl 4-aminobenzoate is iodinated in a methylene
chloride/water (50:50) mixture in the presence of sodium
bicarbonate to provide compound (XCII). This material is coupled to
cyanuric chloride, then the secondary amine is alkylated in an
analogous manner to that in Scheme 1 to yield XCIII. Compound XCIII
is treated with 5 equivalents of MeMgBr to provide the desired
material of formula (XCIV). ##STR38##
Scheme 22 depicts the synthesis of compounds of Formula (I), where
Y=N, Z=CR.sup.2 and R.sup.3 is COR.sup.25, CH(OH)R.sup.25 or
C(OH)R.sup.25 R.sup.25a. An ester of Formula (XCVI) may be
converted to an amide of Formula (C) by treatment with an amine of
Formula HN(OR.sup.a)R.sup.b, where R.sup.a and R.sup.b are lower
alkyl (preferably Me), in the presence of a trialkylaluminum
reagent (preferably Me.sub.3 Al) in an inert solvent preferably an
aromatic hydrocarbon (e.g., benzene) or an ethereal solvent (e.g.,
tetrahydrofuran) as taught by the prior art (cf. J. I. Levin, E.
Turos, S. M. Weinreb, Synthetic Communications 12:989-993 (1982)).
Amides of Formula (C) may be converted to ketones of Formula (CI)
by treatment with an organolithium reagent R.sup.25 Li or an
organomagnesium halide R.sup.25 MgX, where X=Cl, Br or I, in an
inert solvent, preferably an ethereal solvent (e.g., diethyl ether
or tetrahydrofuran), as taught by the prior art (cf. S. Nahm and S.
M. Weinreb, Tetrahedron Letters 22:3815-3818 (1981)).
Alternatively, ketones of Formula (CI) can be prepared from acids
of Formula (XCV) by treatment with an organolithium reagent
R.sup.25 Li in the presence of an inorganic salt (preferably a
transition metal halide (e.g., CeCl.sub.3)) in an inert solvent
(preferably an ethereal solvent (e.g., tetrahydrofuran)) as taught
by the prior art (cf. Y. Ahn and T. Cohen, Tetrahedron Letters
35:203-206 (1994)). Alternatively, esters of Formula (XCVI) can be
converted directly to ketones of Formula (XCVIII) by reaction with
an organolithium reagent R.sup.25 Li or an organomagnesium halide
R.sup.25 MgX, where X=Cl, Br or I, in an inert solvent (preferably
an ethereal solvent e.g., diethyl ether or tetrahydrofuran) at
temperatures ranging from -100 to 150.degree. C. (preferably -78 to
80.degree. C.) (cf. J. March, Advanced Organic Chemistry (New York:
J. Wiley and Sons, 1985, pp.433-434). Ketones of Formula (XCVIII)
can be converted to alcohols of Formula (XCIX) by reaction with an
organolithium reagent R.sup.25 Li or an organomagnesium halide
R.sup.25 MgX, where X=Cl, Br or I, in an inert solvent (preferably
an ethereal solvent (e.g. diethyl ether or tetrahydrofuran) at
temperatures ranging from -100 to 150.degree. C. (preferably -78 to
80.degree. C.) (cf. the above March reference, pp. 434-435).
Alternatively, esters of Formula (XCVI) can be converted to
alcohols of Formula (XCIX) by reaction with an organolithium
reagent R.sup.25a Li or an organomagnesium halide R.sup.25a MgX,
where X=Cl, Br or I, in an inert solvent (preferably an ethereal
solvent e.g., diethyl ether or tetrahydrofuran) at temperatures
ranging from -100 to 150.degree. C. (preferably -78 to 100.degree.
C.), preferably using an excess amount of organometallic reagent
(cf. the above March reference, pp. 434-435). In this last
instance, R.sup.25 =R.sup.25. Ketones of Formula (XCVIII) can be
converted to alcohols of Formula (C) by treatment with a reducing
agent in an inert solvent. Such reducing agents include, but are
not limited to, alkali metal aluminum hydrides, preferably lithium
aluminum hydride, alkali metal borohydrides (preferably sodium
borohydride), alkali metal trialkoxyaluminum hydrides (such as
lithium tri-t-butoxyaluminum hydride), dialkylaluminum hydrides
(such as di-isobutylaluminum hydride), borane, dialkylboranes (such
as di-isoamyl borane), alkali metal trialkylboron hydrides (such as
lithium triethylboron hydride). Inert solvents include lower alkyl
alcohols of 1 to 6 carbons, ethereal solvents (such as diethyl
ether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of
6 to 10 carbons. Reaction temperatures for the reduction range from
about -78.degree. to about 200.degree. C., preferably about
0.degree. to about 120.degree. C. The choice of reducing agent and
solvent is known to those skilled in the art as taught in the above
cited March reference (Advanced Organic Chemistry, pp. 1093-1110).
##STR39##
Compounds of Formula (I) can also be prepared by the procedures
outlined in Scheme 23. A compound of Formula (CI) (Formula I, where
Z=CR.sup.2, Y=N, R.sup.3 =(CHR.sup.11).sub.p CN) can be reacted
with sodium azide and ammonium chloride in a polar solvent at high
temperatures (preferably 70 to 150.degree. C.) to give a tetrazole
of Formula (CII) as taught by the prior art (cf. R. N. Butler,
Tetrazoles, in Comprehensive Heterocyclic Chemistry; A. R.
Katritzky, C. W. Rees, Eds.; (New York: Pergamon Press, 1984), pp.
828-832). Such polar solvents may be dialkylformamides (preferably
N,N-dimethylformamide), dialkylacetamides, (preferably
N,N-dimethylacetamide), cyclic amides, (preferably
N-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethyl
sulfoxide) or dioxane. A compound of Formula (CIII) (Formula I,
where Y=N, Z=CR.sup.2 and R.sup.3 =COCH.sub.3) may be treated with
a halogenating agent in an inert solvent to give a haloketone of
Formula (CIV). Such halogenating agents include bromine, chlorine,
iodine, N-halosuccinimides (e.g. N-bromosuccinimide),
N-halophthalimides (e.g., N-bromophthalimide) or N-tetrasubstituted
ammonium perbromides (e.g., tetraethylammonium perbromide) (cf. the
above March reference, Advanced Organic Chemistry, pp. 539-531; S.
Kajigaeshi, T. Kakinami, T. Okamoto, S. Fujisaki, Bull. Chem. Soc.
Japan 60:1159-1160 (1987) and references cited therein). Inert
solvents include lower halocarbons of 1 to 6 carbons and 2 to 6
halogens (preferably dichloromethane or dichloroethane), dialkyl
ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons
(preferably dioxane) or aromatic hydrocarbons to 6 to 10 carbons.
Haloketones of Formula (CIV) may be converted to imidazoles of
Formula (CVII) by treatment with formamide with or without an inert
solvent as taught by the prior art (H. Brederick and G. Theilig,
Chem. Ber. 86:88-108 (1953)). Alternatively, ketones of Formula
(CIII) may be converted to vinylogous amides (CV) by reaction with
N,N-di(lower alkyl)formamide di(lower alkyl)acetals (e.g.,
N,N-dimethylformamide dimethyl acetal) or Gold's reagent
((dimethylaminomethyleneaminomethylene)-dimethylammonium chloride)
in an inert solvent with or without base as taught by the prior art
(cf. J. T. Gupton, S. S. Andrew, C. Colon, Synthetic Communications
12:35-41 (1982); R. F. Abdulla, K. H. Fuhr, J. Organic Chem.
43:4248-4250 (1978)). Such inert solvents include aromatic
hydrocarbons of 6 to 10 carbons, lower alkyl alcohols of 1 to 6
carbons, dialkyl ethers of 4 to 10 carbons, or cyclic ethers of 4
to 10 carbons (preferably dioxane). Such bases may include a
tertiary amine, an alkali metal hydride (preferably sodium
hydride), an aromatic amine (preferably pyridine), or an alkali
metal carbonate or alkoxide. Vinylogous amides (CV) can be
condensed with hydrazine in an inert solvent to form pyrazoles of
Formula (CVI) as taught by the prior art (cf. G. Sarodnick,
Chemische Zeitung 115:217-218 (1991); Y. Lin, S. A. Lang, J.
Heterocyclic Chem. 14:345 (1977); E. Stark et al., Chemische
Zeitung 101:161 (1977); J. V. Greenhill, Chem. Soc. Reviews 6:277
(1977)). Such inert solvents include aromatic hydrocarbons of 6 to
10 carbons, lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers
of 4 to 10 carbons, or cyclic ethers of 4 to 10 carbons (preferably
dioxane). ##STR40##
The purines and 8-aza-purines of the present invention are readily
synthesized following the methods shown in Schemes 24 and 25. The
purine (CXI) is derived from an appropriately substituted
pyrimidine (CVIII). The trisubstituted hydroxypyrimidine is
nitrated under standard conditions with fuming nitric acid.
Following conversion of the hydroxy compound to the chloro
derivative via treatment with phosphorus oxychloride, reduction of
the nitro group with iron powder in acetic acid and methanol
yielded the aminopyrimidine (CIIX). Compound CIIX is reacted with
the appropriately substituted aniline in the presence of base
catalyst to yield an anilinopyrimidine (CX), which was then
converted to the desired purine (CXI) via reaction with
triethylorthoformate in acetic anhydride. Starting from compound
CX, the desired 8-aza-purine can be prepared via reaction with
sodium nitrite in acetic acid. ##STR41##
If R.sup.3 of the purine is a chloro group, that substituent can be
further elaborated to other R.sup.3 substituents as shown in Scheme
25. Compound (CXII), wherein R.sup.3 is chlorine, is reacted with a
nucleophile with or without an inert solvent at temperatures
ranging from 20.degree. C. to 200.degree. C., to effect the
formation of the 8-azapurine (CXIII). In a similar fashion, the
R.sup.3 of an appropriately substituted purine (CXI) may be
converted to other functional groups to yield the purine (CXIV)
having the desired substitution pattern. Similarly, if R.sup.1 is a
chloro group, it may be converted to another functional group via
reaction with an appropriate nucleophile. Nucleophiles include
amine, hydroxy, or mercapto compounds or their salts. ##STR42##
Compounds of the Formula (I) wherein J, K, and/or L are N, such as
(CXXVII), (CXXVIII), (CXXIX), or (CXXX), were prepared according to
Schemes 26 and 27. The preparation of the lower ring heterocycle of
the compound of the Formula (I) is shown in Scheme 26.
2,4-Dihydroxy-5-nitropyrimidine (CXV) was first converted to the
dichloro compound (CXVI) via treatment with phosphorus oxychloride.
Compound (CXVI) was then converted to the symmetrically
bis-substituted pyrimidines, (CXVII) and (CXVIII), via reaction
with the appropriate R.sup.5 or X group radicals, MR.sup.5 and MX,
respectively, where M is a metal atom. It is understood that
compounds of the Formula (I) wherein R.sup.5 and X have the same
definition fall within the scope of this invention. A method of
forming the unsymmetrically bis-substituted compounds (CXIX) and
(CXX) is treatment of (CXVI) with equimolar amounts of MR.sup.5 and
X to form a statistical distribution of products, (CXVII),
(CXVIII), (CXIX) and (CXX), which can be purified by standard
techniques, such as, recrystallization or chromatography,
The desired (N-pyrimidino-N-alkyl)aminopyrimidines of the present
invention were prepared according to Scheme 27. An appropriately
substituted 2-hydroxypyrimidine (CXXI) was converted to the
2-chloropyrimidine (CXXII) via treatment with phosphorus
oxychloride. The intermediate (N-pyrimidino)aminopyrimidines,
(CXXIII), (CXXIV), (CXXV), and (CXXVI), were prepared via treatment
of (CXXII) with the appropriate 5-aminopyrimidine, (CXVII),
(CXVIII), (CXIX) and (CXX) respectively, in the presence of a base,
such as, NaH. Simple alkylation of the amino groups in (CXXIII),
(CXXIV), (CXXV), and (CXXVI) via treatment with R.sup.4 I and
sodium hydride gave the desired
(N-pyrimidino-N-alkyl)aminopyrimidines, (CXXVII), (CXXVIII),
(CXXIX), and (CXXX). ##STR43## ##STR44##
The (N-heterocycle-N-alkyl)aminopyrimidines or N-heterocycle-N-
alkyl)aminotriazines of the present invention may also be prepared
according to Scheme 28. Commercially available amino substituted
heterocycles (CXXXI) may be brominated using a tetrasubstituted
ammonium tribromide, preferably benzyltrimethylammonium tribromide
(BTMA Br.sub.3) to yield the appropriately substituted
o-bromo-aminoheterocycle (CXXXII). Such reactions are carried out
in an inert solvent, such as, lower alcohols or halocarbons of 1 to
4 carbons and 1 to 4 halogens in the presence of a base, such as,
alkali metal or alkaline earth metal carbonates. Compound (CXXXII)
is then coupled to a substituted pyrimidine or triazine (CXXXIII)
to form an (N-heterocycle)aminopyrimidine (CXXXIVa) or
(N-heterocycle)aminotriazine (CXXXIVb). (CXXXIVa or b) is then
further alkylated in the presence of a base to the target
(N-heterocycle-N-alkyl)aminopyrimidine (CXXXVa) or
(N-heterocycle-N-alkyl)aminotriazine (CXXXVb), respectively.
##STR45##
The compounds of the invention and their syntheses are further
illustrated by the following examples and preparations. All
temperatures are in degrees Celsius.
EXAMPLE 1
N-(2-bromo-4-methylphenyl)-N-methyl-4,6-dimethyl-2-pymidinamine
Part A: To 4,6-dimethyl-2-hydroxypyrimidine (37.1 g), cooled in an
ice bath was slowly added phosphorous oxychloride (60 mL) and the
mixture was stirred at 0.degree. C. for 15 minutes and heated to
reflux for 23 hours. The mixture was allowed to cool to room
temperature, poured slowly over ice and extracted with diethyl
ether (20.times.100 mL). The combined ether layers were dried over
magnesium sulfate and concentrated in vacuo to yield an off-white
crystalline solid (19.77 g). The remaining material was subjected
to lighter-than-water liquid/liquid extraction using diethyl ether
for 19.5 hours to yield additional off-white crystalline solid
(3.53 g) after concentration. A total of 23.31 g of
2-chloro-4,6-dimethylpyrimidine was obtained (55% yield).
Part B: To a solution of the product from Part A (2.0 g) in
ethylene glycol (80 mL) was added 2-bromo-4-methylaniline (2.6 g, 1
eq) and the mixture was heated to reflux for 4.5 hours. After
cooling to room temperature, the mixture was partitioned between
water (200 mL) with ethyl acetate (3.times.100 mL). The ethyl
acetate layers were combined, washed with brine, dried over
magnesium sulfate, and concentrated under vacuum to yield a brown
solid (4.92 g). This product was purified on a silica gel-60 column
using 25% ethyl acetate in hexanes as eluent. The intermediate,
N-(2-bromo-4-methylphenyl)-4,6-dimethyl-2-pyrimidinamine (3.29 g)
was obtained as light tan fine crystals (80% yield).
Part C: To the product from Part B (1.0 g) in dry tetrahydrofuran
(40 mL) was added potassium tert-butoxide in 2-methyl-2-propanol
(1.0 M, 6.8 mL) and iodomethane (1.0 mL, 5 eq). The mixture was
stirred for 72 hours at room temperature. After partitioning
between water (50 ml) using ethyl acetate (2.times.100 ml), the
ethyl acetate layers were combined, washed with brine, dried over
magnesium sulfate, and concentrated in vacuo to yield a yellow
liquid (1.06 g). The crude product was purified on a silica gel-60
column using 15% ethyl acetate in hexanes as eluent. The title
compound, as the free base, was obtained as a thick yellow liquid
(0.89 g; 85% yield). Anal. Calcd C.sub.14 H.sub.16 BrN.sub.3 : % C,
54.92; % H, 5.27; % N, 13.72; ; % Br: 26.09. Found: % C, 54.61; %
H, 5.25; % N, 13.55; % Br; 26.32.
The hydrochloride salt was made using anhydrous hydrogen chloride
in diethyl ether; mp 120-121.degree. C.
EXAMPLE 2
N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pymidinamine
Part A: A mixture of the product from Example 1, Part A (2.01 g,
14.01 mmoles), 2-bromo-4-(1-methylethyl)aniline (3 g, 14.10 mmoles)
in ethylene glycol (20 mL) was heated to reflux for 1.5 hours.
Following cooling to room temperature and partitioning between
ethyl acetate (200 mL) and aqueous sodium hydroxide (1 M, 50 mL),
the organic layer was washed with brine, dried, and concentrated in
vacuo. The residue was chromatographed on silica gel using 5% ethyl
acetate in hexanes to give
2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine(3.28
g).
Part B: The product from Part A (1.64 g, 5.12 mmoles) was treated
with sodium hydride (60% in oil, 0.41 g, 10.25 mmoles) in
tetrahydrofuran (10 mL) at 25.degree. C. for 15 minutes and
iodomethane (0.82 mL, 13 mmoles) was added. The mixture was stirred
at 25.degree. C. for 90 hours and partitioned between ethyl acetate
(100 mL) and water (30 mL). The water was extracted with additional
ethyl acetate (60 mL) and the combined organic extracts were washed
with brine, dried, and concentrated in vacuo. The residue was
chromatographed on silica gel using 8% ethyl acetate in hexanes to
give the title compound (1.4 g) as the free-base.
The free-base was dissolved in ether (10 mL) and treated with a
solution of anhydrous hydrogen chloride in ether (1 M, 6 mL). The
precipitated solid was collected and dried under vacuum (mp
163-164.degree. C.).
EXAMPLE 3
N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pypimidinamine
Part A: 2-Bromo-4-acetylacetanilide (2 g, 7.81 mmoles) was
dissolved in trifluoroacetic acid (20 mL) and triethylsilane (2.8
mL, 17.5 mmoles) was added. The mixture became warm and was stirred
without cooling for 4 h. Then it was basified with conc. NH.sub.4
OH and NaHCO.sub.3 and extracted with EtOAc (2.times.100 mL). The
organic extracts were combined, washed with brine, dried and
stripped in vacuo. The residue was >90% clean and directly used
in the next step.
Part B: Using the product from Part A and the procedure outlined
for Example 1, the desired compound was obtained in good yield.
EXAMPLE 4
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pymidin
amine
Part A: A mixture of 2,4-dichloro-6-methylpyrimidine (4 g, 24.54
mmoles), morpholine (2.14 mL, 24.54 mmoles) and
N,N-diisopropylethylamine (4.52 mL) in ethanol (60 mL) was stirred
at 0.degree. C. for 3 hours, 25.degree. C. for 24 hours, followed
by reflux for 1 hour. The solvent was removed under vacuum and the
residue was partitioned between ethyl acetate (200 mL) and aq.
sodium hydroxide (1 M, 50 mL). The organic layer was washed with
water and brine and dried and concentrated in vacuo. The residue
was recrystallized from ethyl acetate/hexanes to give
2-chloro-4-morpholino-6-methylpyrimidine (3.8 g).
Part B: The product from Part A (1 g, 4.67 mmoles) and
2-bromo-4-(1-methylethyl)aniline (1 g, 4.67 mmoles) were heated to
reflux in ethylene glycol (6 mL) for 1.5 hours. After cooling, the
mixture was partitioned between ethyl acetate (100 mL) and aq.
sodium hydroxide (1 M, 20 mL). The organic layer was washed with
water and brine, dried and concentrated on a rotary evaporator. The
residue was chromatographed on silica gel using 25% ethyl acetate
in hexanes to give
2-N-(2-bromo-4-(1-methylethyl)phenyl)-4-morpholino-6-methylpyrimidinamine
(1.5 g).
Part C: The product from Part B (1.0 g, 2.56 mmoles) was treated
with sodium hydride (60% in oil, 0.15 g, 3.75 mmoles) in
tetrahydrofuran (10 mL) at 25.degree. C. for 20 minutes, followed
by addition of iodoethane (0.32 mL, 4 mmoles). The mixture was
stirred at 25.degree. C. for 24 hours and heated to reflux for 5
hours. After partitioning between ethyl acetate (100 mL) and water
(20 mL), the organic extract was washed with brine, dried, and
concentrated in vacuo. The residue was chromatographed on silica
gel using 12% ethyl acetate in hexanes to give the title compound
(0.94 g) as the free-base.
The hydrochloride salt of the above title compound was prepared by
dissolving the isolate in ether (10 mL) and treating with anhydrous
hydrogen chloride in ether (1 M, 4 mL). The precipitated solid was
collected and dried under vacuum (mp 219-222.degree. C.).
EXAMPLE 5
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinamine
Part A: To a solution of 2-bromo-4-(1-methylethyl)aniline (6 g,
28.2 mmoles) and cyanamide (4.7 g, 112.08 mmoles) dissolved in
ethyl acetate (100 mL) and ethanol (13 mL) was added hydrogen
chloride in ether (1 M, 38 mL, 38 mmoles) and the mixture was
stirred at 25.degree. C. for 1 hour. The volume of the reaction was
reduced by 75 mL by distillation. The residue was heated to reflux
for 3 hours and after cooling, ether (120 mL) was added. The
precipitated solid, 2-bromo-4-(1-methylethyl)phenylguanidinium
hydrochloride, was collected and dried (10.4 g), and was used in
the next reaction without purification.
Part B: A mixture of the product from Part A (5.0 g, 13.47 mmoles),
potassium carbonate (1.86 g, 13.47 mmoles) and 2,4-pentanedione
(2.8 mL, 27.28 mmoles) in N,N-dimethylformamide (35 mL) was heated
to reflux for 24 hours. After cooling, the reaction was partitioned
between ethyl acetate (120 mL) and aq. sodium hydroxide (0.5 M, 100
mL). The aqueous layer was extracted with additional ethyl acetate
(120 mL) and the combined organic extracts were washed with water,
brine, dried and concentrated in vacuo. The residue was
chromatographed on silica gel eluting with 8% ethyl acetate in
hexanes to give
2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine
(3.37 g).
Part C: The product isolated from Part B (3.0 g, 9.37 mmoles) was
alkylated with sodium hydride and iodoethane in tetrahydrofuran in
an analogous manner to that described for Example 4, Part C. The
title compound was isolated as the free-base (2.88 g).
The hydrochloride salt was prepared in a manner analogous to that
of Example 4 using hydrogen chloride in ether, to give a solid, mp
151-153.degree. C.
EXAMPLE 6
N-ethyl-N-(2-bromo-4-(2-methoxyethyl)phenyl)4-morpholino-6-methyl-2-pyrimid
inamine
Part A: To 4-Hydroxyethylaniline, 16.55 g (0.12 moles) in a mixture
of pyridine (23 mL, 0.29 moles) and CH.sub.2 Cl.sub.2 (100 mL)
cooled to 0.degree. C. was added acetyl chloride (18.8 mL, 0.26
moles) dropwise. The mixture was stirred at 0.degree. C. for 2 h
and at 25.degree. C. for 48 h and then added to saturated
NaHCO.sub.3 solution (100 mL). The CH.sub.2 Cl.sub.2 was separated,
washed with brine, dried and stripped in vacuo. The residue was
chromatographed on silica gel using 25% and 1:1 EtOAc/hexanes to
give the product (24 g, 90% yield).
Part B: 4-Acetoxyethylacetanilide was brominated according to the
method described in Org. Synth. Coll. Vol I, 111, wherein the
anilide (14 g, 63 mmoles) was dissolved in glacial acetic acid (70
mL) and bromine (4 mL, 77.4 mmoles) was added dropwise. The
resulting solution was stirred at 25.degree. C. for 60 hours. A
solution of sodium sulfite (20 mL) was then added, followed by
H.sub.2 O (200 mL) and the precipitated bromide was isolated by
filtration. The filtrate was further diluted with H.sub.2 O (300
mL) and cooled to give an additional amount of bromide. The
isolated bromide was heated to reflux in HCl solution (6M, 100 mL)
for 2 h and the resulting mixture was neutralized with solid
NaHCO.sub.3 and extracted with EtOAc (2.times.160 mL each). The
combined EtOAc extracts were washed with brine, dried and stripped
in vacuo. The residue was chromatographed on silica gel using 1:1
EtOAc/hexanes to give the product (2.8 g) in 20% yield for the two
steps.
Part C: 2-Bromo-4-hydroxyethylaniline (1.6 g, 7.3 mmoles) and
2-chloro-4,6-dimethylpyrimidine (1.1 g, 7.3 mmoles) were reacted in
ethylene glycol (6 mL) at reflux for 1.5 h. After cooling the
mixture was partitioned between EtOAc (100 mL) and NaOH solution
(0.5M, 25 mL). The aqueous layer was extracted with additional
EtOAc (50 mL) and the combined organic extracts were washed with
brine, dried and stripped in vacuo. The residue was chromatographed
on silica gel using 1:1 EtOAc/hexanes to give the product (1.3 g)
in 64% yield.
Part D: The product from Part C (1.39 g, 4.77 mmoles) was dissolved
in dry CH.sub.2 Cl.sub.2 (30 mL) and 3,4-dihydro-2H-pyran (1.65 mL,
11.98 mmoles) was added, followed by conc. sulfuric acid (Conc.
H.sub.2 SO.sub.4, 0.2 mL). The mixture was stirred at 25.degree. C.
for 60 h and solid KpCp, (1 g) was added, followed by saturated
NaHCO (50 mL), The mixture was partitioned be tween EtOAc (120 mL)
and NaHCO.sub.3 solution (20 mL). The EtOAc was washed with brine,
dried, and stripped in vacuo. The dried crude product, dissolved in
dry THF (15 mL) was treated with sodium hydride (60% in oil, 380
mg) at 25.degree. C. for 15 min and then iodoethane (1 mL, 9.45
mmoles) was added.
The mixture was stirred at 25.degree. C. for 12 h and heated to
reflux for 4 h. Then it was partitioned between EtOAc (120 mL) and
H.sub.2 O (20 mL). The EtOAc was washed with brine, dried and
stripped in vacuo. The residue was chromatographed on silica gel
using 15% EtOAc/hexanes to give the product (1.6 g) in 78% yield
for the two steps.
Part E: The product from Part D was dissolved in MeOH (20 mL) and
conc. H.sub.2 SO.sub.4 (0.4 mL) was added, followed by HCl in ether
(1M, 1.5 mL). The mixture was stirred at 25.degree. C. for 2 h,
quenched with solid K.sub.2 CO.sub.3 (1 g), and partitioned between
EtOAc (100 mL) and NaHCO.sub.3 solution (30 mL) and NaOH solution
(2 mL, 2 M). The H.sub.2 O layer was extracted with additional
EtOAc (60 mL) and the combined EtOAc extracts were washed with
brine, dried, and stripped in vacuo. The residue was
chromatographed on silica gel using 40% EtOAc/hexanes to give the
product (1.23 g) in 95% yield.
Part F.: The product from Part E (720 mg, 2.06 mmoles) was treated
with NaH (60% in oil, 120 mg, 3 mmoles) in THF (10 mL) at 0.degree.
C. for 5 min and at 25.degree. C. for 15 min. lodomethane (0.25 mL,
4 mmoles) was added and the resulting mixture was stirred at
25.degree. C. for 20 h. The reaction was partitioned between EtOAc
(100 mL) and H.sub.2 O (25 mL). The EtOAc was washed with brine,
dried, and stripped in vacuo. The residue was chromatographed on
silica gel using 20% EtOAc/hexanes to give the product (680 mg)
(91% yield), which was converted into the hydrochloride salt by
treatment with 1 M HCl/ether, mp 117-118.5.degree. C.
EXAMPLE 7
N-Ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-morpholinyl-6-methyl-2-pyrimidin
amine
A solution of the free-based Example 4 (1.4 g, 3.34 mmoles)
dissolved in tetrahydrofuran (15 mL) at -78.degree. C. was treated
with n-butyllithium (1.6 M in hexanes, 3.3 mL, 3.7 mmoles). After
stirring 15 minutes, a solution of iodine (1.0 g, 4 mmoles) in
tetrahydrofuran (5 mL) was added dropwise and the mixture was
stirred at -78.degree. C. for an additional 30 minutes before
warming to 25.degree. C. The reaction was partitioned between ethyl
acetate (100 mL) and sodium bisulfite solution (satd., 20 mL). The
ethyl acetate layer was washed with water, brine, dried and
concentrated in vacuo. The residue was chromatographed on silica
gel using 15% ethyl acetate in hexanes as eluent to give the title
compound (0.9 g) as a solid, mp 96-98.degree. C.
EXAMPLE 8
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(2-thienyl)-2-pyrimi
dinamine
Part A: 2-Chloropyrimidine (2.0 g) was dissolved in diethyl ether
(50 mL) and chilled to -30.degree. C. A solution of methyllithum in
ether (1.4 molar, 15 mL) was slowly added and the reaction was
stirred at -30.degree. C. for 30 minutes, then at 0.degree. C. for
an additional 30 minutes. A mixture of acetic acid (glacial, 1.2
mL), water (0.5 mL) and tetrahydrofuran (5 mL) was added to quench
the reaction. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (4.79 g) in
tetrahydrofuran (20 mL) was then added and the reaction was allowed
to stir for 5 minutes at room temperature. The mixture was chilled
to 0.degree. C. and aqueous sodium hydroxide solution (3 M, 50 mL)
was added and the reaction mixture allowed to stir for 10 minutes.
The organic layer was separated and washed with water and dried
with magnesium sulfate. The solvent was removed in vacuo and the
resulting residue chromatographed on silica gel (solvent 30% ethyl
acetate in hexanes; R.sub.f 0.4) to yield
2-chloro-4-methylpyrimidine (1.4 g), m.p. 48-50.degree. C.
Part B: To thiophene (0.66 g) in dry ether (25 mL) at 0.degree. C.
was added n-butyl lithium in hexanes (1.6 M, 2.7 mL) and the
reaction was stirred at 0.degree. C. for 15 minutes. After cooling
to -30.degree. C., a solution of 2-chloro-4-methylpyrimidine (1.0
g) in ether (10 mL) was slowly added and the reaction was stirred
at -30.degree. C. for 30 minutes and at 0.degree. C. an additional
30 minutes before quenching with a mixture of acetic acid (glacial,
0.45 mL), water (0.5 mL) and tetrahydrofuran (1.0 mL).
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in
tetrahydrofuran (5 mL) was added and the reaction mixture was
stirred at room temperature for 5 minutes, then cooled to 0.degree.
C. before aq. sodium hydroxide solution (3 M, 50 mL) was added. The
organic layer was separated, washed with water, and dried with
magnesium sulfate. The solvent was evaporated and the resultant
crude oil was chromatographed on silica gel (30% ethyl acetate in
hexanes; R.sub.f 0.55) to yield
2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g). Anal. Calcd: %
C, 51.46; % H, 3.33; % N, 13.33. Found: % C, 51.77; % H, 3.35; % N,
12.97.
Part C; 2-Bromo-4-(1-methylethyl)aniline (0.26 g) and
2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g) in ethylene
glycol were heated at reflux for 24 hours. The reaction mixture was
diluted with ethyl acetate, washed with aq. sodium hydroxide
solution (10% , 3.times.100 mL) and the organic phase was dried.
Solvent removal gave a crude brown oil, which was purified on
silica gel using 20% ethyl acetate in hexanes (R.sub.f 0.5) as
eluent to provide
N-(2-bromo-4-isopropylphenyl)-4-methyl-6-(2-thienyl)-2-pyrimidinamine
(0.1 g) as a solid, mp 98-101.degree. C. Mass spec (NH.sub.3
-CI/DDIP): 390 (M+H).sup.30 .
Part D: The product from Part C (0.1 g) was slowly added to a
solution of sodium hydride (50 mg) in dry tetrahydrofuran, after
which iodoethane (0.1 g) was added and the mixture was refluxed for
24 hours. The reaction mixture was cooled and water (0.5 mL) was
added. The solvent was evaporated and the crude material was taken
up in ethyl acetate, washed with water (3.times.50 mL) and dried.
The solvent was evaporated and the crude product chromatographed on
silica gel using 10% ethyl acetate in hexanes (R.sub.f 0.5) to give
the title compound (70 mg) as the free-base.
The HCl salt of this material was prepared using the procedure
reported above; mp 95-97.degree. C.; Mass spec. (NH.sub.3
-CI/DDIP): 417 (M+H).sup.+. Anal. Calcd for C.sub.20,H.sub.22
N.sub.3 BrS.HCl: % C, 53.10; % H, 5.09; % N, 9.51. Found: % C,
53.78; % H, 5.22; % N, 9.10.
EXAMPLE 9
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyri
midinamine)
By analogy to Example 2 the title compound was prepared by
substituting 2-bromo-4-(1-methylethyl)aniline (4.0 g) and
2-chloro-4,6-dimethylpyrimidine in Part A, to give the desired
pyrimidinamine intermediate, Mass spec. (NH.sub.3 -CI/DDIP): 321
(M+H).sup.+. By substituting (bromomethyl)cyclopropane in Part B of
this same Example, the desired material was obtained, Mass spec.
(NH.sub.3 -CI/DDIP): 374 (M+H).sup.+.
The hydrochloride salt of this free base was prepared, mp
146-148.degree. C.
EXAMPLE 10
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-propargyl4,6-dimethyl-2-pyrimidinamin
e
By using
2-(2-bromo-4-(1-methylethyl)anilino)-4,6-dimethylpyrimidine and
substituting propargyl chloride in Example 9, the title compound
was isolated as the free-base, Mass spec. (NH.sub.3 -CI/DDIP): 358
(M+H).sup.+.
The hydrochloride salt of the free base was prepared.
EXAMPLE 11
N-Ethyl-N-(2-iodo4-(2-methoxyethyl)phenyl)4,6-dimethyl-2-pyrimidinamine,
hydrochloride
Part A: 4-Hydroxyethylaniline was iodinated in a manner analogous
to that described in Example 6 in conjunction with that reported in
Tet. Lett. 33:373-376 (1992). The aniline (2 g, 14.58 mmoles) was
dissolved in CH.sub.3 CN (25 mL) and H.sub.2 O (15 mL) containing
NaHCO.sub.3 (1.68 g, 20 mmoles) was added. The mixture was cooled
to 12-15.degree. C. by addition of ice and iodine (3.9 g, 15.35
mmoles) was added. The mixture was stirred at 25.degree. C. for 16
h and then it was partitioned between EtOAc (100 mL) and NaOH
solution (20 mL, 1M). The EtOAc was washed with brine, dried and
stripped in vacuo. The residue was chromatographed on silica gel
using 1:1 EtOAc/hexanes to give 1.8 g product, a 47% yield.
Part B: The product from Part A (6.3 g, 23.94 mmoles) was dissolved
in a mixture of EtOAc (100 mL) and EtOH (10 mL) and cyanamide (4.7
g, 112.5 mmoles) was added, followed by HCl in ether (31 mL, 1 M).
The flask was fitted with a distillation head and 50 mL solvent was
distilled off. The residual mixture was diluted with EtOH (15 mL)
and heated to reflux for 5 h. After cooling, Et.sub.2 O (100 mL)
was added and the precipitated salt was washed with EtOAc and dried
to give the product (4.5 g) in 55% yield.
Part C: The guanidinium salt from Part B (8.53 g, 24.95 mmoles),
potassium carbonate (3.84 g, 27.72 mmoles) and 2,4-pentanedione (9
mL, 42.65 mmoles) were heated to reflux in DMF (70 mL) for 16 h.
The reaction mixture was partitioned between EtOAc (150 mL) and
H.sub.2 O (50 mL) and the organic layer was washed with H.sub.2 O
(2.times.80 mL), brine, dried and stripped in vacuo. The residue
was chromatographed on silica gel using 1:1 EtOAc/hexanes to give
the product (2.8 g) in 30% yield.
Part D: To the product from Part C (3.3 g (8.93 mmoles) in CH.sub.2
Cl.sub.2 (60 mL) and 3,4-dihydro-2H-pyran (3.1 mL, 22.7 mmoles) was
added Conc. H.sub.2 SO.sub.4 (0.5 mL) and the mixture was stirred
at 25.degree. C. for 16 h. An additional portion of H.sub.2
SO.sub.4 (0.2 mL) was added and stirring was continued for 3 h.
EtOAc (100 mL) and saturated NaHCO.sub.3 (100 mL) was added and the
layers separated. The aqueous layer was extracted with additional
EtOAc (100 mL) and the combined organic extracts were washed with
NaHCO.sub.3, brine, dried and stripped in vacuo. The residue was
chromatographed on silica gel using 20% EtOAc/hexanes to give the
product (1.2 g) in 31% yield.
Part E: The product from Part D was dissolved in dry THF (15 mL)
and NaH (60% in oil, 220 mg, 5.5 mmoles) was added. The mixture was
stirred at 25.degree. C. for 15 min and iodoethane (0.5 mL, 5.7
mmoles) was added. The mixture was stirred at 25.degree. C. for 16
h and then heated to reflux for 2 h. The reaction product was then
partitioned between EtOAc (100 mL) and H.sub.2 O (30 mL). The
organic layer was washed with brine, dried and stripped in vacuo.
The residue was chromatographed on silica gel using 10%
EtOAc/hexanes to give the product (1.1 g). This material was
dissolved in MeOH (20 mL). HCl in ether (3 mL, 1M) was added and
the mixture was stirred at 25.degree. C. for 2 h. Then it was
partitioned between EtOAc (100 mL) and NaOH (30 mL, 1 M). The EtOAc
was washed with brine, dried and stripped in vacuo. The residue was
used in the next step without purification.
Part F: The product from Part E (950 mg, 2.4 mmoles) in dry THF (10
mL) was treated with NaH (60% in oil, 140 mg, 3.5 mmoles), stirred
at 25.degree. C. for 15 min and 0.25 mL lodoethane (4 mmoles) was
added. The resulting mixture was stirred at 25.degree. C. for 16 h
and then partitioned between EtOAc (100 mL) and H.sub.2 O (20 mL).
The organic layer was washed with brine, dried and stripped in
vacuo. The residue was chromatographed on silica gel using 20%
EtOAc/hexanes to give the product (500 mg), which was converted
into the hydrochloride salt in the usual manner, mp 129-131.degree.
C.
EXAMPLE 12
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pymidinamine
Part A: The product from Example 8, Part A (0.2 g) and
2-bromo-4-(1-methylethyl)aniline were coupled using the same method
described in Example 8, Part C to provide
N-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-2-pyrimidinamine (0.7
g) as a viscous oil; Mass spec. (NH.sub.3 -CI/DDIP): 307 (M+H).
Part B: The product from Part A was alkylated with iodoethane using
the same method described in Example 8, Part D to give the desired
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine
(0.3 g) as the free base.
The hydrochloride salt of this material was prepared in the usual
manner; mp 145-147.degree. C. Mass spec. (NH.sub.3 -CI/DDIP). 334
(M+H).sup.+.
EXAMPLE 13
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxye
thlamino)-2-pyrimidinamine
Part A: A solution of 2,4-dichloro-6-methylpyrimidine (1.0 g) and
2-(methylamino)ethanol (0.4 g) in ethanol (50 mL) was refluxed for
24 hours. The solvent was evaporated to give a crude residue, which
was chromatographed on silica gel using 5% methanol in chloroform
to yield
2-chloro-4-methyl-6-(N-methyl-2-hydroxyethylamino)pyrimidine (370
mg).
Mass spec. (NH.sub.3 -CII/DDIP): 202 (M+H).sup.+.
Part B: The hydroxyl group in the product from Part A was protected
as the methoxymethyl ether (MOM-ether) using
N,N-di(1-methylethyl)ethylamine and bromomethyl methyl ether (0.35
g) in dry tetrahydrofuran to provide the protected adduct (310 mg,
Mass spec. 246 (M+H).sup.+), which was carried on without
purification.
Part C: The protected MOM-ether was coupled with
2-bromo-4-(1-methylethyl)aniline using the procedure of Example 8,
Part C. Under these conditions, the methoxymethyl protecting group
was also removed providing
N-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-6-(N-methyl-2-hydroxyethylami
ne)-2-pyrimidinamine (mass spec. NH.sub.3 -CI/DDIP 379
(M+H).sup.+). This hydroxyl group was reprotected for subsequent
reactions as described in Part B, (Mass spec. for MOM-ether
(NH.sub.3 -CI/DDIP): 453 (M+H).sup.+). Alkylation with iodoethane
was carried out using the method of Example 8, Part D. The
MOM-ether was deprotected by stirring at room temperature in a
solution of methanol (5 mL) and hydrochloric acid (1 M, 5 mL) for
24 hours. Upon workup and isolation, the title compound was
obtained as the free-base.
The hydrochloride salt was prepared using the described procedure.
High Res. Mass Spec; 407.144640 (M+H).sup.+ ; Expected 407.144648
(M+H).sup.+.
EXAMPLE 14
N-ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimi
dinamine, S-oxide
The desired product was obtained by sodium periodate oxidation of
the product of Example 22, according to the method of J. H.
Bushweller et. al. J. Org. Chem. 54:2404, (1989).
EXAMPLE 15
N-(2-Bromo-4-(isopropoxy)phenyl)-N-ethyl-4,6dimethyl-2-pymidinamine
Part A: The synthesis of 2-bromo-4-isopropoxy-aniline was
accomplished using the bromination procedure for
4-isopropoxy-aniline reported by Kajigaeshi et al. in Bull. Chem.
Soc. Jpn. 61:597-599 (1988). The aniline, 1 eq.
benzyltrimethylammonium tribromide, and 2 eq. calcium carbonate
were stirred at room temperature in a solution of MeOH:CH.sub.2
Cl.sub.2 (2:5) for one hour. The solids were removed by filtration
and the filtrate was evaporated under vacuum. The residue was taken
up in H.sub.2 O and this mixture was then extracted three times
with CH.sub.2 Cl.sub.2. The combined extracts were dried over
MgSO.sub.4, filtered, and evaporated under vacuum to give a brown
oil, which was purified on silica gel using 15% EtOAc in hexanes.
(R.sub.f =0.43)
Part B: Using the procedure for Example 1, Parts B-C and
substituting the aniline from Part A, the title compound was
obtained.
EXAMPLE 16
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbon
yl)-2-pyrimidinamine
To sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in
anhydrous THF (10 mL) was added morpholine (0.52 g, 6.0 mmol) with
stirring; the reaction mixture was warmed to reflux temperature and
stirred for 1 hour. The reaction mixture was then cooled to ambient
temperature and
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-py
rimidine (2.0 g, 5.1 mmol) was added. Stirring was continued for 26
hours. The reaction mixture was then poured onto a 1N NaOH
solution, stirred and extracted three time with EtOAc. The combined
organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo. Column chromatography (Et.sub.2 O) afforded
the title compound as a solid (900 mg, 39% yield): mp 145.degree.
C.; NMR (CDCl.sub.3, 300 MHz):d 7.5 (d, 1H, J=1), 7.2 (dd, 1H,
J=7,1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3
(m, 11H), 3.1-3.0 ( m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H,
J=7), 1.15 (t, 3H, J=7); Anal. (C.sub.21 H.sub.27 BrN.sub.4
O.sub.2) Calcd: C, 56.38; H, 6.08; N, 12.52; Br, 17.86; Found: C,
56.07; H, 6.05; N, 12.29; Br, 18.08.
EXAMPLE 17
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylmethyl
)-2-pyrmidinamine
A solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbo
nyl)-2-pyrimidinamine (750 mg, 1.72 mmol) in anhydrous THF (1.4 mL)
was stirred at ambient temperature under a nitrogen atmosphere. A
solution of borane in THF (1 M, 3.6 mL, 3.6 mmol) was added
dropaise. The reaction mixture was then warmed to reflux
temperature and stirred for 20 hours. After cooling to room
temperature, acetic acid (3.5 mL) was added slowly and the mixture
was heated to reflux temperature and stirred for 30 min. After
being cooled to ambient temperature, the reaction mixture was
poured onto a 3N NaOH solution, mixed and extracted three times
with EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo. Column chromatography (EtOAc)
of the residue afforded the title compound as an oil (300 mg, 39%
yield, R.sub.f 0.3): NMR (CDCl.sub.3, 300 MHz): d 7.5 (s, 1H), 7.2
(d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 ( s, 1H), 4.3-4.1 (m, 1H),
3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H),2.9 (septet, 1H, J=7), 2.55-2.35
(br m, 3H), 2.35-2.25 ( m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7);
CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.
EXAMPLE 18
Methyl
2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarbo
xylate
To sodium hydride (60% in oil, 4.8 g, 120 mmol) in THF (150 mL) at
ambient temperature under a nitrogen atmosphere was added
methyl-2-((2-bromo-4-(1-methylethyl)phenyl)amino)-6-methyl-4-pyrimidinecar
boxylate (42.8 g, 118 mmol) portionwise over 30 min. After the gas
evolution subsided, iodoethane (31.2 g, 16 mL, 200 mmol) was added
in one portion and the reaction mixture was heated to a gentle
reflux for 24 h. After cooling to room temperature, the reaction
mixture was quenched carefully with water and extracted three times
with ethyl acetate. The combined organic extracts were washed with
water twice, dried over magnesium sulfate and filtered. Solvent was
removed in vacuo to afford a brown oil. Column chromatography of
the oil (Et.sub.2 O:hexanes::1:1) provided two fractions: (1)
methyl-2-((2-bromo-4-(1-methylethyl)phenyl)amino)-6-methyl-4-pyrimidinecar
boxylate (4.6 g, 11% yield, R.sub.f =0.8) and (2) the title product
(20 g, R.sub.f =0.7) as a crude oil. The title product was
recrystallized from hexanes and dried in vacuo to give a solid
(18.0 g, 39% yield): mp 81-82.degree. C.: NMR(CDCl.sub.3, 300
MHz):d 7.5 (br s, 1H), 7.25 (d, 1H, J=7), 7.15 (d, 1H, J=7), 7.1
(s, 1H), 4.3-4.1 (m, 1H), 4.05-3.75 (m, 4H), 2.95 (septet, 1H,
J=7), 2.3 (br s, 3H), 1.3 (d, 6H, J=7), 1.25 (t, 3H, J=7); CI-HRMS:
calcd: 392.0974 (M+H), found: 392.0960.
EXAMPLE 19
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-methylpiperazinyl
carbonyl)-2-pyrimidinamine
Using a method analogous to that used for Example 16, but
substituting 4-methylpiperazine, the desired product was obtained;
mp 81-82.degree. C.
EXAMPLE 20
N-(2-Bromo-4-(2-hydroxyethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The THP-hydroxyl protecting group was removed using HCl in ether
product as described earlier to arrive at the title compound; mp
58-60.degree. C.
EXAMPLE 21
N-ethyl-N-(2-methoxy4-(1-methylethyl)phenyl)4,6-dimethyl-2-pyimidinamine
Part A: Using the method of Example 1 and substituting
2-amino-5-methylphenol, the intermediate secondary amine was
obtained.
Part B: By double methylating the amino and the phenol groups using
excess sodium hydride and iodomethane in THF, the desired product
was obtained.
EXAMPLE 22
N-ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimi
dinamine
Using the iodination method of Example 11 and the general synthesis
described in Example 4 the desired compound was obtained; mp
51-53.degree. C.
EXAMPLE 23
N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,
5-triazin-2-amine
Part A: Methyl magnesium bromide (300 mmole, 3M in ether, Aldrich)
was added dropwise over a 10 min period to a solution of cyanuric
chloride (12.9 g, 69.9 mmole) in CH.sub.2 Cl.sub.2 (300 mL) under
N.sub.2 at -20.degree. C. and stirring was continued at -20.degree.
C. for 4.5 hours. Water (36 mL) was added dropwise while keeping
the reaction temperature below -15.degree. C. The reaction mixture
was allowed to reach room temperature and magnesium sulfate (40 g)
was added. It was let stand for one hour. The reaction mixture was
filtered and the solvent removed leaving a yellow solid (11.06 g).
This material was purified using flash chromatography (CH.sub.2
Cl.sub.2, silica) and gave 2,4-dichloro-6-methyl-s-triazine as a
white solid (7.44 g) in 65% yield.
Part B: 2,4-dichloro-6-methyl-s-triazine (3 g, 18.29 mmol),
2-bromo-N-ethyl-4-isopropylaniline (6.07 g, 25.07 mmol) and
diisopropylethylamine (3.2 g, 25.07 mmol) in dioxane (60 mL) under
N.sub.2 were heated at reflux for three hours. The solvent was
removed and the residue was purified using flash chromatography
(CH.sub.2 Cl.sub.2, silica) to provide the product (4.58 g) as a
clear oil in 68% yield.
Part C: The product from Part B (500 mg, 1.35 mmol) was dissolved
in dioxane (20 mL) under N.sub.2 at room temperature and morpholine
(247 mg, 2.84 mmol) was added in one portion. Stirring was
continued at room temperature for 17 hours. The reaction solvent
was stripped away and the residue was triturated with ethyl
acetate/hexane (1:3). The triturated material was purified using
flash chromatography (EtOAc/hexane, 1:3 Silica). The product was
collected as a clear oil (550 mg) in 97% yield. C.sub.19 H.sub.26
N.sub.3 OBr
EXAMPLE 24
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-m
ethyl-6-(hydroxymethyl)-2-pyrimidinamine
The product of Example 18 and lithium borohydride (1.5 eq.) were
stirred in dry THF under nitrogen for fifty hours. The reaction was
then poured into water and extracted three times with CHCl.sub.3.
The combined extracts were dried over MgSO.sub.4, filtered, and
evaporated under vacuum to give a nearly quantitative yield of the
product as a light yellow oil.
EXAMPLE 25
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methoxymethyl)-2-py
rimidinamine
To the product of Example 24 and sodium hydride (1.1 eq.) in dry
THF under nitrogen was added iodomethane (1.1 eq.) and after four
hours the reaction was poured into H.sub.2 O and extracted three
times with CHCl.sub.3. The combined extracts were dried over
MgSO.sub.4, filtered, and evaporated under vacuum. The material was
purified by chromatography on silica gel using 10% EtOAc in hexanes
to give a light yellow oil. (R.sub.f =0.37)
Example 26
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine
Part A: 2-Bromo-4-isopropylaniline (8.9 g, 42 mmol) and
6-hydroxy-4-methyl-2-thiomethylpyrimidine (5 g, 32 mmol) were
combined under N.sub.2 and heated at 190.degree. C. for 8 hours.
The reaction mixture was cooled to room temperature. The residue
was purified using flash chromatography (CH.sub.2 Cl.sub.2 /MeOH,
25:1, silica) to provide 9.16 g (89% yield) white solid.
Part B: The product from Part A (6 g, 18.6 mmol) and phosphorus
oxychloride (20 mL, 214 mmol) were refluxed under N.sub.2 for 15
minutes. The reaction mixture was cooled to room temperature,
slowly poured onto ice (200 g), stirred about 30 minutes until the
ice had melted, and the aqueous mixture was extracted with ethyl
acetate (3.times.100 mL). The combined organic extracts were
treated with water (100 mL) and brine (100 mL), dried over
anhydrous sodium sulfate, filtered and stripped leaving 6.1 g tan
oil. This material was purified using flash chromatography
(CH.sub.2 Cl.sub.2 /hexane, 1:1, silica) to give 4.48 g (70% yield)
of clear oil.
Part C: To the product of Part B (4.3 g, 12.65 mmol) in
dimethylformamide (30 mL) under N.sub.2 was added sodium hydride
(658 mg, 16.45 mmol, 60% dispersion in oil) was added in small
portions. After addition was complete, stirring was continued 4
hours at room temperature. Water (100 mL) was added to the reaction
mixture and it was extracted with ethyl acetate (3.times.100 mL).
The combined organic extracts were treated with water (100 mL) and
brine (100 mL). The organic layer was dried over anhydrous sodium
sulfate, filtered and stripped leaving 4.8 g tan oil. This material
was purified using flash chromatography (EtOAc/hexane, 1:6, silica
gel) to afford 4.4 g (95% yield) of oil.
Part D: The product of Part C (2 g, 5.4 mmol) and sodium
thiomethoxide (558 mg, 7.6 mmol) in dioxane (50 mL) under N.sub.2
were heated to reflux (20 hrs.). The solvent was stripped and the
residue was purified using flash chromatography (CH.sub.2 Cl.sub.2
/hexane, 1:1, silica) to give 1.86 g (91% yield) of clear oil.
Analysis: MS (NH3--CI/DDIP) : 380 (M+H).sup.+.
EXAMPLE 27
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine, dioxide
To the product of example 26 (1.8 g=4.8 mmol) in CH.sub.2 Cl.sub.2
(100 mL) under N.sub.2 was added 3-chloroperbenzoic acid (3.16 g,
14.67 mmol, 80-85% purity) in small portions and after addition,
stirring was continued for 30 minutes. Unreacted peroxide was
consumed using 10% sodium sulfite (5 mL), and the reaction mixture
was diluted with CH.sub.2 Cl.sub.2 (150 mL) followed by washing
with 5% sodium bicarbonate (100 mL) and brine (100 mL). The organic
layer was dried over anhydrous sodium sulfate, filtered and
stripped leaving 2.19 g yellow oil. This material was purified
using flash chromatography (CH.sub.2 Cl.sub.2, silica) to provide
1.6 g of oil (79% yield). MS (NH3-CI/DDIP): 412 (M+H).sup.+.
EXAMPLE 28
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrim
idinamine, S-oxide
To Example 26 product (770 mg, 2 mmol) in methanol (200 mL) was
added sodium periodate (648 mg, 3 mmol) in water (10 mL) in one
portion and the reaction mixture was refluxed 28 hours. The
reaction solvent was stripped away and the residue was partitioned
between ethyl acetate (200 mL) and water (50 mL). The organic layer
was separated and treated with brine (50 mL). The organic layer was
dried over anhydrous sodium sulfate, filtered and stripped leaving
820 mg tan residue. This material was purified using flash
chromatography (EtOAc/hexane, 1:1, silica) to afford 570 mg (71%
yield) of oil. MS (NH3-CI/DDIP) : 396 (M+H).sup.+.
EXAMPLE 29
N-[2-bromo-4(1-methylethyl)phenyl]-N-ethyl-4-methyl-6-benzyloxy-1,3,5
triazin-2-amine
Benzyl alcohol (197 mg, 1.82 mmol, 1.2 eq) was added slowly to a
solution of NaH (73 mg 60% dispersion, 1.82 mmol) in dry DMF and
stirred at room temperature for 15 minutes. The product from Part B
(560 mg, 1.52 mmol) was then added and the resulting mixture
stirred at room temperature for 2 hours, The reaction mixture was
then poured into water and extracted three times with ethyl
acetate. The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo. The crude oil was
chromatographed on silica using 20% ethyl acetate in hexanes as
solvent to afford the title compound. C.sub.22 H.sub.25 N.sub.4 OBr
Calcd: C, 55.46; H, 5.46; N, 11.76; Found: C, 55.30; H, 5.41; N,
12.02.
EXAMPLE 30
N-[2-iodo-4-dimethylhydroxymethylphenyl]-N-ethyl-4-6-dichloro-1,3,5
triazin-2-amine
Part A: Ethyl 4-aminobenzoate (5.0 gr, 30.27 mmol) and sodium
bicarbonate (3.81 g, 45.40 mmol, 1.5 eq.) were added to a 50:50
mixture of methylene chloride and water. The mixture was chilled to
0 degrees and I.sub.2, (11.53 g, 45.40 mmol, 1.5 eq.) was added
slowly. The reaction mixture was allowed to come to room
temperature and was stirred for 72 hours. The layers were then
separated and the aqueous layer washed with methylene chloride. All
organics were combined and dried over magnesium sulfate, filtered
and concentrated in vacuo. The resulting oil was chromatographed on
silica using 30% ethyl acetate in hexanes as solvent to afford
ethyl 3-iodo-4-aminobenzoate. C.sub.9 H.sub.10 NO.sub.2 I MS 292
(M+H).sup.+ 309 (M+NH.sub.4).sup.+.
Part B: The product from part A (1.0 g, 3.4 mmol) was added to a
stirring solution of NaH (0.21 gr, 5.2 mmol) in 25 mL of dry DMF
and allowed to stir at room temperature for 10 minutes. Ethyl
iodide (0.8 g, 5.2 mmol) was then added and the mixture was allow
to stir for 24 hours. The reaction was then poured into water and
extracted with ethyl acetate. The organic layer was dried with
magnesium sulfate, filtered, and concentrated in vacuo. The crude
material was chromatographed on silica using 30% ethyl vacuo. The
crude material was chromatographed on silica using 30% ethyl
acetate in hexanes as solvent to afford ethyl
3-iodo-4-(N-ethyl)aminobenzoate. C.sub.11 H.sub.14 NO.sub.2 I MS
320(M+H).sup.+.
Part C: The product from part B (0.32 g, 1.0 mmol) was dissolved in
dioxane and cyanuric chloride (0.18 g, 1.0 mmol) was added slowly.
The reaction was heated to reflux for 4 hours, stirred at room
temperature for 24 hours, then poured into water and extracted with
ethyl acetate. The organic layer was dried with magnesium sulfate,
filtered, and concentrated in vacuo. The crude material was
chromatographed on silica using 10% ethyl vacuo. The crude material
was chromatographed on silica using 10% ethyl acetate in hexanes as
solvent to afford
N-[2-iodo-4-ethylcarboylate]-N-ethyl-4-6-dichloro-1,3,5triazin-2-amine.
C.sub.14 H.sub.13 N.sub.4 O.sub.2 C.sub.2 I MS 467 (M+H).sup.+.
Part D: The product of part C (0.26 g, 0.6 mmol) was dissolved in
20 mL methylene chloride and chilled to -20 degrees. Methyl
magnesium slowly. The reaction was allowed to come to room
temperature and stirred for 4 hours, then poured into water and the
layers were separated. The aqueous layer was extracted with
methylene chloride and the organic layers combined, dried with
magnesium sulfate, filtered, and concentrated in vacuo. The crude
material was chromatographed on silica gel using 30% ethyl acetate
in hexanes as solvent to afford the title compound. C.sub.15
H.sub.18 N.sub.4 OICl MS 453 (M +H).sup.+.
EXAMPLE 31
N-(2-iodo4-(1-methylethyl)phenyl)-N-allyl4-morpholino-6-methyl-2-pyrimidina
mine
mp 109-112.degree. C. Elemental analysis for C.sub.21 H.sub.27
N.sub.4 IO HCl: Theory C, 48.99; H, 5.48; N, 10.88; I, 24.65; Cl,
6.89. Found C, 48.81; H, 5.43; N, 10.59, I, 24.67; Cl, 6.86.
EXAMPLE 32
N-(2-iodo4-(1-methylethyl)phenyl)-N-ethyl-4-chloro-6-methyl-2-pyrimidinamin
e
Guanidine 39.5 mmoles crude, obtained by treatment of the
corresponding guanidinium salt with K.sub.2 CO.sub.3, 15 mL (118
mmoles) ethyl acetoacetate and 2.0 g (14.47 mmoles) K.sub.2
CO.sub.3 were heated to reflux in 120 mL absolute ethanol for 100
hr. Then the solvent was stripped in vacuo and the residue was
chromatographed on silica gel using 40% EtOAc/hexanes as eluent to
give 4 g product, a 27% yield for the three steps.
The 4-hydroxypyrimidine obtained from the above reaction (2.47 g,
6.69 mmoles) was dissolved into 20 mL POCl.sub.3 and stirred at
25.degree. C. for 4 hr. The reaction mixture was poured into ice,
stirred for 30 min, and extracted with 100 mL EtOAc. The EtOAc
extract was washed with brine, dried and stripped in vacuo. The
residue was chromatographed on silica gel using 20% EtOAc/hexanes
to give 1.64 g of the corresponding 4-chloropyrimidine (63%
yield).
1.6 g (4.13 mmoles) 4-chloropyrimidine obtained above, and 0.33 g
(8.25 mmoles) of NaH (60% in oil) in 10 mL dry DMF at 25.degree. C.
were stirred together for 15 min. Then 0.7 mL (8.75 mmoles) of EtI
was added and the reaction was stirred at 0.degree. C. for 2 h and
at 25.degree. C. for 16 h. It was then partitioned between 100 mL
EtOAc and 25 mL water and the EtOAc was washed with water
(2.times.30 mL), brine, dried and stripped in vacuo. The residue
was chromatographed on silica gel using 8% EtOAc/hexanes to give
1.2 g product as a viscous liquid (70% yield); elemental analysis
for C.sub.16 H.sub.19 N.sub.3 ClI: Theory: C, 46.23; H, 4.61; N,
10.11; Cl, 8.53; I, 30.53. Found: C, 46.36; H, 4.57; N, 9.89; Cl,
8.79; I, 30.38.
EXAMPLE 33
N-(2-methylthio4-(1-methylethyl)phenyl)-N-ethyl-4(S)-(N-methyl-2'-pyrrolidi
nomethoxy)-6-methyl-2-pyrimidinamine
The chloropyrimidine described above, 0.66 g (1.59 mmoles), 70 mg
(1.76 mmoles) of NaH (60% in oil) and 0.19 mL (1.6 mmoles)
(S)-N-methylprolinol in 10 mL of dry THF under nitrogen were
stirred at 25.degree. C. for 36 h and then refluxed for 2h. The
mixture was partitioned between 10 mL EtOAc and 20 mL water and the
EtOAc was washed with water, brine, dried and stripped in vacuo.
The residue was chromatographed on silica gel using 0.5% NH.sub.4
OH/5% CH.sub.3 OH/CH.sub.2 Cl.sub.2 as eluent to give 340 mg
product, which was converted into the dihydrochloride salt by
treatment with 1 M HCl in ether, mp 101-103.degree. C. (dec).
Elemental analysis for C.sub.22 H.sub.31 N.sub.4 IO. 2HCl: Theory
C, 46.57; H, 5.86; N, 9.88; Cl, 12.50. Found C, 46.69; H, 6.02; N,
9.45; Cl, 12.69.
EXAMPLE 34
N-(2,6-dibromo-4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimidi
namine
580 mg (2.46 mmoles) of
2-chloro-4-thiomorpholino-6-methylpyrimidine, 793 mg (2.7 mmoles)
of2,6-dibromo-4-isopropylaniline and 216 mg (5.4 mmoles) of NaH
(60% in oil) were refluxed in toluene for 6 hr and purified by
silica gel chromatography using 25% EtOAc/hexanes (79% yield); mp
194-195.degree. C. Elemental analysis for C.sub.18 H.sub.22 N.sub.4
Br.sub.2 S: Theory C, 44.46; H, 4.56; N, 11.52; Br: 32.87; S,6.59.
Found: C, 44.67; H, 4.54; N, 11.24; Br: 32.8; S, 6.62.
EXAMPLE 35
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine
The product was synthesized by lithium-bromine exchange of the
appropriately substituted 2-bromo-4-isopropylanilinopyrimidine with
nBuLi in THF at 0.degree. C. followed by reaction with
dimethyldisulfide. It was purified by silica gel chromatography
using 8% EtOAc/hexanes as eluent, (37% yield); mp 64-66.degree. C.
Elemental analysis for C.sub.18 H25N.sub.3 S: C, 68.53; H, 7.99; N,
13.32; S, 10.16. Found: C, 68.43; H, 7.94; N, 13.16; S, 10.02.
EXAMPLE 36
N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinami
ne
The hydrochloride salt of Example 35, was formed in the usual
manner; mp 141-142.degree. C. Elemental analysis for C.sub.18
H.sub.25 N.sub.3 S HCl: Theory C, 61.43; H, 7.45; N, 11.94; S,
9.11; Cl, 10.07. Found: C, 61.07; H, 7.40; N, 11.80; S, 9.37; Cl,
9.77.
EXAMPLE 37
N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine
The sulfide of Example 35, (300 mg, 0.95 mmoles), was reacted with
300 mg (1.41 mmoles) NaIO.sub.4 in 6 mL MeOH and 3 mL water at
25.degree. C. for 24 h. The reaction mixture was partitioned
between 100 mL EtOAc and 25 mL water and the EtOAc extract was
washed with water, brine, dried and stripped in vacuo. The residue
was purified by silica gel chromatography using 1:1 EtOAc/hexanes
as eluent to give 220 mg product, (70% yield); mp 144-146.degree.
C. Elemental analysis for C.sub.18 H.sub.25 N.sub.3 O.sub.5 :
Theory C, 65.22; H, 7.60; N, 12.68; S, 9.67. Found: C, 65.12; H,
7.63; N, 12.48; S, 9.71.
EXAMPLE 38
N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiazolidino-6-methyl-2-pyrimi
dinamine
The title compound was obtained as a viscous liquid. Elemental
analysis for C.sub.19 H.sub.25 N.sub.4 IS: Theory C, 48.72; H,
5.38; N, 11.96; S, 6.84; I, 27.09. Found: C, 48.80; H, 5.36; N,
11.84; S, 6.95; I, 27.05.
EXAMPLE 39
N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The title compound was obtained as a viscous liquid. Elemental
analysis for C.sub.16 H.sub.20 N.sub.3 IO: Theory C, 48.37; H,
5.08; N, 10,58. Found C, 48.27; H, 5.00; N, 10.07.
EXAMPLE 40
N-(4,6-dimethyl-2-pyrimidinamino)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-
benzothiazepine
To 4 grams, (15.32 mmoles) of 2-iodo-4-isopropylaniline, and 2.53 g
(18.4 mmoles) of 4,6-dimethyl-2-mercaptopyrimidine in 30 mL DMF,
were added 4.8 g (34.4 mmoles) of K.sub.2 CO.sub.3 and 600 mg (9.2
mmoles) of Cu powder and the resulting mixture was heated to reflux
for 2 h. After cooling, 30 mL EtOAc was added and the solids were
filtered off. The filtrate was partitioned between 200 mL EtOAc and
50 mL water and the EtOAc layer was washed with water (3.times.60
mL), brine, dried and stripped in vacuo to provide an oily residue
that was used without further purification; MS(m/e) 275 (M+2, 20%);
274 (M+1, 100%).
To 0.6 g (2.2 mmoles) of the above crude product in 8 mL dry
xylenes was added 132 mg (3.3 mmoles) NaH (60% in oil) and the
mixture was heated to reflux for 5 h. Then 0.22 mL (2.2 mmoles) of
1,3-dibromopropane was added and the reaction was heated for
another 2 h. Another 60 mg (1.2 mmoles) NaH (60% in oil) was added
and heating was continued for another 3 h. After cooling the solids
were filtered off, the solvent removed in vacuo, and the filtrate
chromatographed on silica gel using 8% EtOAc/hexanes to give 220 mg
product (32% yield for the two steps); High res MS: calc
314.169095; measured: 314.168333. This was converted into the
hydrochloride salt by treatment with 1M HCl in ether, mp
157-159.degree. C.
EXAMPLE 41
N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine
The sulfoxide of Example 37, (100 mg, 0.3 mmoles) was stirred in 4
mL of CH.sub.2 Cl.sub.2 and 8 mL water with 20 mg (0.09 mmole) of
benzyltriethylammonium chloride and 94.5 mg (0.6 mmole) KMnO.sub.4
at 25.degree. C. for 16 h. The mixture was partitioned between 60
mL EtOAc and 40 mL water and the EtOAc was washed with water,
brine, dried and stripped in vacuo. The residue was purified by
silica gel chromatography using 25% EtOAc/hexanes to give 85 mg
product (81% yield); mp 174-175.3.degree. C. Elemental analysis for
C.sub.18 H.sub.25 N.sub.3 O.sub.2 S: Theory C, 62.22; H, 7.25; N,
12.09; S, 9.23. Found: C, 62.13; H, 7.28; N, 11.93; S, 9.12.
EXAMPLE 42
N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinamin
e
The title compound was prepared in the same manner as the product
of Example 36; mp 128-130.degree. C. Elemental analysis for
C.sub.19 H.sub.27 N.sub.3 S HCl: Theory C, 62.36; H, 7.71; N,
11.48; S, 8.76; Cl, 9.69. Found: C, 62.64; H, 7.75; N, 11.43; S,
8.59; Cl, 9.58.
EXAMPLE 43
N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine
The title compound was prepared in the same manner as the product
of Example 44; mp 77-78.degree. C. Elemental analysis for C.sub.19
H.sub.26 N.sub.4 OS: Theory C, 63.66; H, 7.31; N, 15.63; S, 8.95.
Found C, 63.70; H, 7.32; N, 15.64; S, 8.94.
EXAMPLE 44
N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidin
amine
To 4 g (29.6 mmoles) of 4'-aminoacetophenone in 20 mL CH.sub.2
Cl.sub.2 and 50 mL water containing 3.6 g (42 mmoles) NaHCO.sub.3
was added 9.0 g (35.4 mmoles) of I.sub.2. The mixture was stirred
at 25.degree. C. for 20 h. Then 20 mL of saturated aqueous Na.sub.2
SO.sub.3 was added and the mixture was stirred for 10 min and
partitioned between 120 mL EtOAc and 10 mL water. The EtOAc extract
was washed with brine, dried and stripped in vacuo and the residue
chromatographed on silica gel using 25% EtOAc/hexanes as eluent to
give 6.1 g product (79% yield).
To 3.05 g (11.69 mmoles) of 4'-amino-3'-iodoacetophenone in a
mixture of 40 mL ethanol and 10 mL 3M NaOH was added 2.10 g (25.20
mmoles) methoxyamine hydrochloride and the mixture was heated to
reflux for 2 h. The ethanol was stripped off in vacuo, the residue
was partitioned between 100 mL EtOAc and 30 mL water and the EtOAc
was washed with water, brine, dried and stripped in vacuo. The
residue was chromatographed on silica gel using 20% EtOAc/hexanes
to give 2.8 g product (83% yield).
The above product 1.5 g (5.18 mmoles) was coupled with
4,6-dimethyl-2-mercaptopyrimidine as described above, to give the
corresponding adduct in 70% yield, after chromatographic
purification.
The above product, 1.1 g (3.64 mmoles) was treated with 190 mg
(4.73 mmoles) NaH (60% in oil) in 7 mL dry xylenes at reflux for
5.5 hours. The reaction mixture was then partitioned between 100 mL
EtOAc and 20 mL water and the EtOAc was washed with water, brine,
dried and stripped in vacuo. The residue was purified by silica gel
chromatography using 25% EtOAc/hexanes to give 900 mg product (82%
yield).
The above product, 900 mg (2.98 mmoles) was treated with 470 mg
(3.4 mmoles) K.sub.2 CO.sub.3 and 0.22 mL (3.54 mmoles) CH.sub.3 I
at 25.degree. C. for 4 h. Then it was partitioned between 100 mL
EtOAc and 20 mL water, the EtOAc was washed with brine, dried and
stripped in vacuo. The residue was used for the next reaction
without further purification.
The above product, 940 mg (2.97 mmoles) was treated with 160 mg
(4.0 mmoles) NaH (60% in oil) in 7 mL dry DMF for 20 min at
25.degree. C. and then 0.32 mL (4.0 mmoles) EtI was added. The
mixture was stirred at 25.degree. C. for 16 h and partitioned
between 100 mL EtOAc and 20 mL water, the EtOAc was washed with
brine, dried, stripped in vacuo and the residue was chromatographed
on silica gel using 20% EtOAc/hexanes to give 600 mg product (58%
yield); mp 106-108.degree. C. Elemental analysis for C.sub.18
H.sub.24 N.sub.4 OS: Theory C, 62.76; H, 7.02; N, 16.27; S, 9.31.
Found C, 62.75; H, 7.03; N, 16.12; S, 9.45.
EXAMPLE 45
N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrim
idinamine
The sulfide obtained from the sequence described above (0.3 g, 0.87
mmoles) was dissolved in 10 mL CH.sub.2 Cl.sub.2 and 0.53 g (2.61
mmoles) of m-chloroperbenzoic acid (mCPBA 85%) was added and the
mixture was stirred at 25.degree. C. for 16 min. The reaction
mixture was quenched with Na.sub.2 SO.sub.3 and partitioned between
40 mL CH.sub.2 Cl.sub.2 and 30 mL 5% NaHCO.sub.3. The organic layer
was dried, stripped in vacuo and the residue was chromatographed on
silica gel using 40% EtOAc/hexanes to give 430 mg product, a 40%
yield, mp 151-154.degree. C. Elemental analysis for C.sub.18
H.sub.24 N.sub.4 O.sub.3 S: Theory C, 57.43; H, 6.43; N, 14.88; S,
8.52. Found: C, 57.24; H, 6.40; N, 14.18; S, 8.60.
EXAMPLE 46
N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
2-Iodo-4-bromoaniline was coupled with
4,6-dimethyl-2-mercaptopyrimidine in 93% yield. One gram of the
adduct (3.22 mmoles) was dissolved in 10 mL methanol and 4 mL (4
mmoles) 1 M HCl in ether was added. The mixture was stirred at
25.degree. C. for 2 h, the solvent was stripped in vacuo and the
residue was partitioned between 150 mL of an 1:1 mixture EtOAc and
CH.sub.2 Cl.sub.2 and 80 mL satd. NaHCO.sub.3. The organic layer
was dried and stripped in vacuo to give 900 mg of the disulfide
product, which was dissolved in 10 mL absolute ethanol and cooled
to 0.degree. C. To that solution 110 mg (2.92 mmoles) of NaBH.sub.4
was added and the mixture was allowed to warm to 25.degree. C. and
stirred for 20 min before 0.36 mL (5.76 mmoles) CH.sub.3 I was
added and the mixture was stirred at 25.degree. C. for 2 h. The
solvent was stripped in vacuo and the residue was partitioned
between 100 mL EtOAc and 30 mL satd. NaHCO.sub.3. The EtOAc was
washed with brine, dried and stripped in vacuo. The residue was
chromatographed on silica gel using 20% EtOAc/hexanes to give 840
mg product, 80% yield for the two steps. MS(m/e): 326 (M+3, 100%);
324 (M+1, 93%).
This was ethylated under the conditions described above in 90%
yield, mp91-93.degree. C. Elemental analysis for C.sub.15 H.sub.18
BrN.sub.3 S: Theory C,51.15; H, 5.15; N, 11.93; Br, 22.68; S, 9.10.
Found C, 51.25; H, 5.15; N, 11.89; Br, 22.42; S, 9.22.
EXAMPLE 47
N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)4,6-dimethyl-2-pyrimidinami
ne
The title compound was prepared in a manner similar to the product
of Example 46; mp 85-87.degree. C. Elemental analysis for C.sub.18
H.sub.25 N.sub.3 S: Theory C, 68.53; H, 7.99; N, 13.32; S, 10.16.
Found: C, 68.56; H, 8.08; N, 13.24; S, 10.27.
EXAMPLE 48
N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The title compound was prepared in a manner similar to the product
of Example 46; mp 140-141.degree. C. Elemental analysis for
C.sub.17 H.sub.23 N.sub.3 S.HCl: Theory C, 60.43; H, 7.16; N,
12.44; S, 9.49; Cl, 10.49. Found C, 60.42; H, 6.89; N, 12.36; S,
9.61; Cl, 10.63.
EXAMPLE 49
N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-py
rimidinamine
The title compound was prepared in a manner similar to the product
of Example 46; mp 158-160.degree. C. Elemental analysis for
C.sub.18 H.sub.24 N.sub.4 OS: Theory C, 62.76; H, 7.02; N, 16.26;
S, 9.31. Found C, 62.67; H, 7.07; N, 16.24; S, 9.56.
EXAMPLE 50
N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The title compound was prepared in a manner similar to the product
of Example 46; mp 99-100.degree. C. Elemental analysis for C.sub.18
H.sub.23 N.sub.3 O.sub.2 S: Theory C, 62.58; H, 6.71; N, 12.16; S,
9.28. Found C, 62.83; H, 6.78; N, 12.08; S, 9.44.
EXAMPLE 51
N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
A mixture of 352 mg (1 mmole)
4-bromo-2-methylmercaptoanilinopyrimidine, 14.3 mg (0.1 mmole) CuBr
and 0.5 mL (2.5 mmoles) 25% w/w MeONa in MeOH was heated to reflux
in 5 mL dry DMF for 1.5 h. The reaction mixture was partitioned
between 100 mL EtOAc and 30 mL water and the EtOAc layer was washed
with water (2.times.30 mL), brine, dried and stripped in vacuo. The
residue was chromatographed on silica gel using 20% EtOAc/hexanes
to give 210 mg product (69% yield); mp 128-130.degree. C. Elemental
analysis for C.sub.16 H.sub.21 N.sub.3 OS.1/4H.sub.2 O: Theory C,
62.41; H, 7.07; N, 13.64; S, 10.41. Found C, 62.06; H, 6.97; N,
13.26; S, 10.47.
EXAMPLE 52
N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The title compound was prepared in a manner similar to the product
of Example 51; mp 112-113.degree. C. Elemental analysis for
C.sub.16 H.sub.18 N.sub.4 S: Theory C, 64.40; H, 6.08; N, 18.78; S,
10.74. Found: C, 64.28; H, 6.16 N, 18.58; S, 11.08.
EXAMPLE 53
N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
To 0.5 g (1.68 mmoles) of the nitrile of Example 52 in 10 mL dry
C.sub.6 H.sub.6 was added 1.1 mL (3.3 mmoles) of a 3 M solution
CH.sub.3 MgI in ether and the mixture was stirred at 25.degree. C.
for 2 h and at reflux for 1 h. The reaction was quenched with water
and 10% HCl and stirred for 20 min before 1 M NaOH was added until
the solution was alkaline and the mixture was extracted with 100 mL
EtOAc. The organic layer was washed with water, brine, dried and
stripped in vacuo. The residue was chromatographed on silica gel
using 20% EtOAc/hexanes to give 370 mg product (70% yield); mp
125-126.degree. C. Elemental analysis for C.sub.17 H.sub.21 N.sub.3
OS: Theory C, 64.73; H, 6.71; N, 13.32; S, 10.16. Found C, 64.53;
H, 6.73; N, 13.08; S, 10.19.
EXAMPLE 54
N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
The title compound was prepared in a manner similar to the product
of Example 53; mp 139-141.degree. C. Elemental analysis for
C.sub.18 H.sub.23 N.sub.3 OS: Theory C, 65.62; H, 7.04; N, 12.75;
S, 9.73. Found C, 65.33; H, 7.19; N, 12.51; S, 9.62.
EXAMPLE 55
N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidina
mine
To 1.05 g (3.33 mmoles) of the ketone of Example 53 in 20 mL
absolute ethanol cooled to 0.degree. C. was added 127 mg (3.32
mmoles) NaBH.sub.4 and the mixture was allowed to warm to
25.degree. C. and stirred for 16 h. Then the solvent was stripped
in vacuo and the residue was partitioned between 100 mL EtOAc and
30 mL 0.3 M NaOH. The EtOAc was washed with water, brine, dried and
stripped in vacuo. The residue was chromatographed on silica gel
using 2:1 EtOAc/hexanes to give 1 g product; mp 46-49.degree. C.
The above alcohol, 0.72 g (2.27 mmoles), was reacted with 108.09 mg
(2.7 mmoles) of NaH (60% in oil) in 5 mL dry DMF at 25.degree. C.
for 20 min and then 0.3 mL (4.8 mmoles) of CH.sub.3 I was added.
The mixture was stirred for 20 h and an additional 60 mg (1.5
mmoles) of NaH (60%) was added, as well as 0.1 mL CH.sub.3 I and
the mixture was stirred for an additional 16 h. It was then
partitioned between 100 mL EtOAc and 30 mL water and the EtOAc was
washed with water (2.times.30 mL), brine, dried and stripped in
vacuo. The residue was chromatographed on silica gel using 20%
EtOAc/hexanes to give 600 mg product as a viscous liquid. This was
converted into the hydrochloride salt by treatment with 1 M HCl in
ether, mp 120-122.degree. C.
EXAMPLE 56
N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinam
ine
A solution of 0.2 g (0.58 mmole)
4-N-acetyl-N-methyl-2-methylmercaptoanilinopyrimidine, in 10 mL
ethanol and 2 mL water containing 272 mg (5 mmoles) KOH was
refluxed for 4 h. An additional 200 mg of KOH was added and the
heating was continued for 3 h. The ethanol was stripped in vacuo
and the residue was partitioned between 100 mL EtOAc and 30 mL
water. The EtOAc extract was washed with brine, dried and stripped
in vacuo. The residue was chromatographed on silica gel using 1:1
EtOAc/hexanes to give 140 mg product, an 80% yield, mp
141-142.degree. C. Elemental analysis for C.sub.16 H.sub.22 N.sub.4
S: Theory C, 63.54; H, 7.33; N, 18.52; S, 10.60. Found C, 63.63; H,
7.41; N, 18.55; S, 10.80.
EXAMPLE 57
N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimid
inamine
To 0.36 g (1.2 mmoles) 4-N-methyl-2-methylmercaptoanilinopyrimidine
in 4 mL dry DMF was added 60 mg (1.5 mmoles) NaH (60% in oil) and
the mixture was stirred for 20 min before 0.1 mL (1.67 mmoles)
CH.sub.3 I was added and the reaction was continued at 25.degree.
C. for 16 h. It was then partitioned between 100 mL EtOAc and 20 mL
water. The EtOAc extract was washed with water, brine, dried and
stripped in vacuo. The residue was chromatographed on silica gel
using 20% EtOAc/hexanes to give 150 mg product (40% yield); mp
119-120.degree. C. Elemental analysis for C.sub.17 H.sub.24 N.sub.4
S: Theory C, 64.52; H, 7.64; N, 17.70; S, 10.13. Found C, 64.55; H,
7.65; N, 17.50; S, 10.31.
EXAMPLE 58
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinam
ine
Example 23 product (453 mg, 1.2 mmol) and manganese dioxide (1.7g,
20 mmol) were heated to reflux in 25 mL dichloromethane for three
days. The reaction was filtered through a pad of Celite, and the
filtrate was concentrated in vacuo to give a light yellow oil. The
oil was purified by silica gel chromatography using 10% ethyl
acetate in hexanes to yield 112 mg of a white solid. CI-HRMS:
calcd: 362.0868 (M+H), found: 362.0864.
EXAMPLE 59
N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-
2-pyrimidinamine
Compound XLVII from Scheme 12 above (0.41 g, 0.92 mmol) and sodium
borohydride (76 mg, 2 mmol) in 10 mL ethanol were stirred for 21
hours at room temperature. The reaction was acidified with 1.0 N
hydrochloric acid, stirred for ten minutes, basified with 1.0 N
sodium hydroxide and extracted with dichloromethane. The combined
extracts were dried with magnesium sulfate and stripped in vacuo to
yield a clear oil which was chromatographed on silica gel using 30%
ethyl acetate in hexanes to give 345 mg product (92% yield).
CI-HRMS: calcd: 408.1287 (M+H), found: 408.1284.
EXAMPLE 60
N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
N-(2-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
(214 mg, 0.58 mmol) in 15 mL dichloromethane under nitrogen was
cooled in a dry ice/acetone bath, and boron tribromide (1.0 M in
dichloromethane, 0.58 mL) was slowly added. The reaction was
allowed gradually to warm to room temperature whereupon it was
stirred overnight. After quenching with water, the aqueous portion
was basified with saturated sodium bicarbonate and extracted with
dichloromethane. The combined extracts were dried with magnesium
sulfate and concentrated in vacuo to give a tan solid. The solid
was recrystallized from ethyl acetate/hexanes to yield 58 mg
product; mp 157-160.degree. C. Anal. Calcd: %C, 51.15; %H, 5.15;
%N, 11.93; %Br, 22.69. Found: %C, 51.02; %H, 5.10; %N, 11.83; %Br,
22.52.
EXAMPLE 61
N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
Part A (Synthesis of 3-bromo-4,6-dimethoxy aniline): To a mixture
of 2,4-dimethoxy aniline (5.0 g, 33 mmol) and potassium carbonate
(10.4 g, 75 mmol) in 30 mL chloroform was slowly added bromine
(5.27 g, 33 mmol) in 20 mL chloroform. After stirring two hours the
reaction was washed three times with water, dried with magnesium
sulfate, and concentrated in vacuo to give a dark solid. The
material was purified by chromatography on silica gel using 20%
ethyl acetate in hexanes to yield 1.77 g product as a tan solid
(23% yield).
Part B: Using the procedure for Example 1; Parts B-C and
substituting the aniline from Part A above, the title compound was
obtained.
EXAMPLE 62
N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
Part A (Synthesis of 2,3dibromo-4,6-dimethoxy aniline):
2,4-dimethoxy aniline, 1 eq. benzyltrimethylammonium tribromide,
and 2 eq. calcium carbonate were stirred at room temperature in a
solution of methanol:dichloromethane (2:5) for one hour. The
solution was filtered, the filtrate was evaporated under vacuum,
and the residue taken up in water and extracted three times with
dichloromethane. The combined extracts were dried over magnesium
sulfate, filtered, and evaporated under vacuum to give a brown oil,
which was purified on silica gel using 20% ethyl acetate in
hexanes. (Rf=0.2)
Part B: Using the procedure for Example 1; Parts B-C and
substituting the aniline from Part A above, the title compound was
obtained.
EXAMPLE 63
N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine
Part A: The synthesis of 2,6-dibromo-4-ethoxy-aniline was
accomplished using the bromination procedure for 4-ethoxy-aniline
reported by Kajigaeshi et. al. in Bull. Chem. Soc. Jpn. 61:597-599
(1988). The aniline, 1 eq. benzyltrimethylammonium tribromide, and
2 eq. calcium carbonate were stirred at room temperature in a
solution of MeOH:CH.sub.2 Cl.sub.2 (2:5) for one hour. The solids
were collected, the filtrate was evaporated under vacuum, and the
residue taken up in H.sub.2 O and extracted three times with
CH.sub.2 Cl.sub.2. The combined extracts were dried over
MgSO.sub.4, filtered, and evaporated under vacuum to give a brown
oil, which was purified on silica gel using 10% EtOAc in
hexanes.
Part B: Using the procedure for Example 1; Parts B-C and
substituting the aniline from Part A above, the title compound was
obtained.
EXAMPLE 64
1-(2-Bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole
Part A: A solution of 42.80 g (0.200 mole) of the potassium salt of
formyl-succinonitrile (K. Gewald, Z. Chem., 1:349 (1961)) and 29.20
g (0.200 mole) of 2-bromo-4-isopropylaniline in a mixture of 50 mL
of glacial acetic acid and 120 mL of ethanol was refluxed (nitrogen
atmosphere) for two hours. The mixture was stripped of most of the
acetic acid and ethanol and the residue was taken up in ethyl
acetate. This solution was washed with 10% sodium bicarbonate
solution, dried with anhydrous sodium sulfate, and evaporated to
give a dark, oily residue, which was chromatographed on silica gel
with 80:20 hexane-ethyl acetate to give 24.23 g (40%) of
N-(2-bromo-4-isopropylphenyl)-aminomethylene-succinonitrile. Mass
spec: (m+NH.sub.4).sup.+ =321.0; calculated, 321.0.
Part B: To a solution of 10 mL of 1M potassium tert-butoxide in
tetrahydrofuran and 10 mL of ethanol was added 1.11 g (3.65 mmole)
of N-(2-bromo-4-isopropyl-phenyl)-aminomethylene-succinonitrile
(Part A). The mixture was stirred for 16 hrs under a nitrogen
atmosphere. The solvents were removed by evaporation. The residue
was taken up in ethyl acetate and washed successively with 1 N
hydrochloric acid, 10% sodium bicarbonate solution, and brine. The
solution was dried with anhydrous sodium sulfate and evaporated to
give a dark residue. The residue was dissolved in dichloromethane,
20 g of silica gel was added, and the mixture was evaporated to
dryness. This mixture was placed on top of a chromatographic column
of 150 g of silica gel in hexane. The column was eluted
successively with 10, 15, 20, 25; and 30% ethyl acetate in hexane
to give 0.65 g (59% yield) of
1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole. Mass spec:
(m+H).sup.+ =304.0; calculated, 304.0. The R.sub.f =0.22 on silica
gel thin layer chromatography by elution with 70:30 hexane-ethyl
acetate. The preparation was scaled up for Part C.
Part C: A mixture of 18.51 g (0.0609 mole) of
1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole, 300 mL of
ethanol, 0.6 mL of conc. hydrochloric acid, and 10 mL (9.75 g,
0.0974 mole) of 2,4-pentanedione was refluxed with stirring under a
nitrogen atmosphere for 4 hrs. The mixture was allowed to cool and
the solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate. The solution was washed with 10% sodium
bicarbonate solution, then with brine. The solution was dried with
anhydrous sodium sulfate and evaporated to give 21.76 g of dark,
tarry residue. The residue was chromatographed on silica gel by
eluting in step gradients of 0, 10, 15, 20, 25; and 30% ethyl
acetate in hexane. The initial fraction is 17.6 g (78%)
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;
m.p. 105.8.degree.. Mass spec: (m+H).sup.+ =368.0749; calculated,
368.0762 (.sup.79 Br). R.sub.f =0.45 on silica gel thin layer
chromatography with 70:30 hexane-ethyl acetate.
EXAMPLE 65
1-(2-Bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole
A mixture of 4.00 g of
1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole and
40 mL of 65% sulfuric acid was refluxed for one hour. The solution
was cooled and poured onto ice. Conc. ammonium hydroxide was added
until the mixture was alkaline to pH paper. The mixture was
extracted with ethyl acetate. The solution was dissolved in 60:40
hexane-ethyl acetate and passed through a short column of silica
gel. The eluate was evaporated, and the residue was crystallized
from 20 mL of hexane to give 2.45 g (66% yield) of
1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole. Mass spec:
(m+H).sup.+ =343.0818; calculated, 343.0810. R.sub.f =0.57 on
silica gel with 70:30 hexane-ethyl acetate.
EXAMPLE 66
1-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole
A mixture of 737 mg (2.00 mmole) of the product from Example 64
(Part B), 324 mg (2.00 mmole) of benzoylacetone and 25 mL of xylene
was heated in a flask equipped with a water separator for 2 hours.
The solvent was removed by evaporation, and the residue
chromatographed on silica gel, eluting in step gradients with 0, 5,
10; and 15% ethyl acetate in hexane. Both
1-(2-bromo-4-isopropylphenyl)-3-cyano-4-methyl-6-phenyl-7-azaindole
and
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-methyl-7-azaindole
were obtained. The R.sub.f values were respectively 0.38 and 0.28
(silica gel with 80:20 hexane-ethyl acetate). The assignment of the
structures was based on the nmr data of the de-cyanylated compounds
in Example 67.
EXAMPLE 67
1-(2-Bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole
A mixture 130 mg (0.302 mmole) of
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole
(Example 66) and 10 mL of 65% sulfuric acid were refluxed for one
hour. The mixture was poured onto ice, Conc. ammonium hydroxide was
added until the mixture was basic to pH paper. The mixture was
extracted with ethyl acetate. The extract was evaporated and
chromatographed on silica gel with 70:30 hexane-ethyl acetate.
There was obtained 112 mg (92% yield) of
1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole. Mass
spec: (m+H).sup.+ =405.10; calculated, 405.10.
In the same way,
1-(2-bromo-4-isopropylphenyl)-4-methyl-6-phenyl-7-azaindole was
obtained, mp 95.8.degree..
EXAMPLE 68
1-(2-Bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole
Part A:
N-(2-bromo-4,6-dimethoxyphenyl)-aminomethylene-succinonitrile was
prepared from 2-bromo-4,6-dimethoxyaniline by the method described
in Example 64, Part A. Mass spec: (m+H).sup.+ =322.0; calculated,
322.16. R.sub.f =0.19 (silica gel with 60:40 hexane-ethyl
acetate).
Part B: The product from Part A was cyclized by the method
described in Example 64, Part B to give
1-(2-bromo-4,6-dimethoxy-phenyl)-2-amino-4-cyano-pyrrole (79%
yield). R.sub.f =0.19 (silica gel with 60:40 hexane-ethyl
acetate).
Part C: The product from Part B was treated with 2,4-pentanedione
as described in Example 64, Part C to give
1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole
(92% yield). Mass spec: (m+H).sup.+ =388.0; calculated, 388.0.
R.sub.f =0.44 (silica gel with 60:40 hexane-ethyl acetate).
EXAMPLE 69
1-(2-bromo-4,6-dimethoxyphenyl,)-4,6-dimethyl-7-azaindole
A mixture of 200 mg of
1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole
and 10 ml of 65% sulfuric acid was refluxed for one hour. The
mixture was worked up as described in Example 65 to give 185 mg of
crude product. A 40 mg portion was purified by preparative liquid
chromatography on a nitrile column using 95:5
1-chlorobutane-acetonitrile to give 11 mg of
1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole. Mass
spec: (m+H).sup.+ =360.9; calculated, 361.1.
EXAMPLE 70
1-(2-Bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole
Part A: A solution of 3.04 g of the product of Example 64 (Part B),
1.9 mL (1.94 g; 14.9 mmole) of ethyl acetoacetate, and 0.1 mL of
conc. hydrochloric acid in 30 mL of ethanol was refluxed for 16
hours. A precipitate formed upon cooling. The precipitate was
removed by filtration to give 1.68 g of crystals; mp 202.4.degree.
C., of 1-(2-bromo-4-isopropylphenyl)-4-methyl-7-azaindole-6-one.
TLC on silica gel with 70:30 hexane-ethyl acetate showed a single
spot, R.sub.f =0.29. Mass spec. (m+H).sup.+ =370.5; calcd., 370.05
(.sup.79 Br).
Part B: A mixture of 185 mg of the 7-azaindole-6-one (Part A) and
50 ml of phosphorus oxychloride was heated in an autoclave at
180.degree. C. for 10 hrs. The excess phosphorus oxychloride was
removed by distillation at reduced pressure. The residue was
distributed between ethyl acetate and water. The ethyl acetate
layer was separated and washed with 10% sodium bicarbonate
solution, then with brine. The solution was dried (Na.sub.2
SO.sub.4) and evaporated. TLC of the residue on silica gel with
70:30 hexane-ethyl acetate showed a major new product, R.sub.f
=0.52 with minor spots at R.sub.f 0.45 and 0.29. Chromatography on
silica gel with step gradients of 5, 10, 15, and 20% ethyl acetate
in hexane gave 109 mg of the R.sub.f 0.52 product; mp 123.8.degree.
C. This is
1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole.
EXAMPLE 71
1-(2-Bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-aziandole
A mixture of 52 mg of
1-(2-bromo-4-isopropyphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole
and 10 mL of 65% sulfuric acid was refluxed for one hour. The
cooled solution was poured onto ice, and 17 mL of conc. ammonium
hydroxide was added. The alkaline mixture was extracted with ethyl
acetate. The extract was washed (brine), dried (Na.sub.2 SO.sub.4),
and evaporated. TLC of the residue on silica gel with 70:30
hexane-ethyl acetate showed a major new spot, R.sub.f =0.58; with a
trace of unchanged starting material (R.sub.f 0.52). The crude
product was purified by preparative TLC to give 39 mg of
non-crystaline product, which slowly crystallized on standing. Mass
spec. (m+H).sup.+ =363.0247; calcd., 363.0264 (.sup.79 Br, .sup.35
Cl).
EXAMPLE 72
1-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole
To a solution of 1.085 g (5.07 mmole) of the product from Example
64 (part B) and 0.80 mL (0.797 g; 6.03 mmole) of acetoacetaldehyde
dimethyl acetal in 20 mL of ethanol was added 0.10 mL of conc.
hydrochloric acid. The mixture was refluxed for 16 hours, then
cooled and evaporated to give a dark, thick oil. TLC on silica gel
with 70:30 hexane-ethyl acetate showed two major spots at R.sub.f
0.47 and 0.41. The oil was dissolved in ethyl acetate, 20 mL silica
gel powder was added, and the mixture was evaporated to dryness.
The powdery residue was loaded on top of a column of 60 mL of
silica gel in hexane. The column was eluted in step gradients of 0,
5, 10, 15, 20, and 25% ethyl acetate in hexane. The first fraction
to elute was 0.32 g of the desired
1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole, Rf
0.47. The material can be crystallized from hexane to give 176 mg
of crystals; mp 176.0.degree. C. Mass spec. (m+H).sup.+ =354.0595;
calcd., 354.0606.
EXAMPLE 73
1-(2-Bromo-4-isopropylphenyl)-6-methyl-7-azaindole
Material from Example 72 was treated with 65% sulfuric acid as
described in Example 65 to give the desired product as a viscous
oil. TLC on silica gel with 70:30 hexane-ethyl acetate showed Rf
=0.57. Mass spec. (m+H).sup.+ =329.0641; calcd., 329.0653 (.sup.79
Br).
EXAMPLE 74
1-(2-Bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole
Part A: A solution of 1.24 g of
1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole
(Example 72) and 1.42 g of 85% 3-chloro-peroxybenzoic acid in 20 mL
of chloroform was refluxed for 6 hrs. The mixture was cooled and
washed first with 10% sodium bicarbonate solution, then with brine.
The solution was dried (Na.sub.2 SO.sub.4) and evaporated to give a
residue. TLC on silica gel with 95:5 dichloromethane-methanol
showed a trace spot at R.sub.f 0.88 and a major spot at R.sub.f
0.34. The material was purified by chromatography on silica gel
with dichoromethane, followed by 1% methanol in dichloromethane, to
give a trace of unchanged
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole (R.sub.f
0.88) and 0.92 g of
1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole 7-oxide
(R.sub.f 0.34); mp 179.2.degree.. Mass spec. (m+H).sup.+ =370.0559;
calcd., 370.0555 (.sup.79 Br).
Part B: A mixture of 370 mg of the 7-oxide (Part A) and 5 mL of
phosphorus oxychloride was refluxed for two hours. The solution was
cooled, poured on ice, and stirred until most of the phosphorus
oxychloride was hydrolysed. The mixture was made alkaline with
conc. ammonium hydroxide and extracted with ethyl acetate. The
extract was dried (Na.sub.2 SO.sub.4) and evaporated to give a
viscous residue. TLC on silica gel with 95:5
dichloromethane-methanol showed a major spot at R.sub.f =0.79. The
material was purified by preparative TLC on silica gel with 70:30
hexane-ethyl acetate to give crystals. Recrystallization from
hexane gave 158 mg of
1-(2-bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole;
mp 123.3.degree. C. Mass spec. (m+H).sup.+ =388.0197; calcd.,
388.0216 (.sup.79 Br, .sup.35 Cl).
EXAMPLE 75
1-(2-Bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole
A mixture of 190 mg of the 3-cyano-7-azaindole (Example 71) and 5
mL of 65% sulfuric acid was refluxed for 30 minutes. The solution
was poured onto ice and extracted with ethyl acetate. The extract
was washed with brine, dried (Na.sub.2 SO.sub.4), and evaporated to
give a residue. TLC of the residue on silica gel with 60:40
hexane-ethyl acetate showed a major spot at R.sub.f =0.67. The
residue was purified by preparative TLC to give 130 mg of a viscous
oil, which is
1-(2-Bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole. Mass
spec. (m+H).sup.+ =363.0246; calcd., 363.0264 (.sup.79 Br, .sup.35
Cl).
EXAMPLE 76
N-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine
Part A: To 3.18 grams (25.6 mmol) of commercially available
5-amino-2-methoxypyridine in a solution of methylene chloride (50
ml) and methanol (20 ml) was added benzyltrimethylammonium
tribromide (10 g, 25.6 mmol) and the mixture was stirred at room
temperature for 24 hours. The solvent was then stripped and the
resulting residue was taken up in water and extracted (3.times.100
mL) with ethyl acetate. The organic extracts were dried with
magnesium sulfate, filtered, and concentrated in vacuo. The crude
material was chromatographed on silica using 30% ethyl acetate in
hexanes as solvent to afford 5-amino-2-bromo-6-methoxypyridine.
C.sub.6 H.sub.7 N.sub.2 OBr MS 203 (M+H).sup.+.
Part B: The product of part A above was coupled to
2-chloro-4,6-dimethylpyrimidine (Example 1; part A) using NaH (1.2
eq) in DMF to give
N-[2-bromo-6-methoxy-pyridin-3-yl]-4,6-dimethyl-2-pyrimidinamine.
C.sub.12 H.sub.13 N.sub.4 OBr MS 309 (M+H).sup.+.
Part C: The product of part B above was alkylated in the same
manner as used in Example 4; part C to provide the title compound.
C.sub.14 H.sub.17 N.sub.4 OBr MS 337 (M+H).sup.+.
EXAMPLE 77
N-[3-bromo-5-methyl-pyridin-2-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine
Part A: A 1.0 gram (5.35 mmol) portion of commercially available
2-amino-3-bromo-5-methylpyridine was coupled to
2-chloro-4,6-dimethylpyrimidine (Example 1; part A) using NaH (1.2
eq) in DMF to give
N-[3-bromo-5-methyl-pyridin-2-yl]-4,6-dimethyl-2-pyrimidinamine.
C.sub.12 H.sub.13 N.sub.4 Br MS 293 (M+H).sup.+.
Part B: The product of part A was alkylated in the same manner as
used in Example 4; part C to provide the title compound. C.sub.14
H.sub.17 N.sub.4 Br MS 321 (M+H).sup.+.
EXAMPLE 78
N-[6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine
To 200 mg of
N-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine
in 25 ml dry DMF was added 500 mg K.sub.2 CO.sub.3, 100 mg of CuI,
and 0.4 mL of morpholine and the reaction was heated to reflux for
6 hour. The reaction mixture was then filtered and poured into
water and then extracted with ethyl acetate (3.times.50 mL). The
extracts were dried and the solvent removed and the resulting
residue was chromatographed on silica gel with 20% ethyl acetate in
hexane as the solvent (rf 0.4) to provide the title compound.
C.sub.14 H.sub.18 N.sub.4 O MS 259 (M+H).sup.+.
EXAMPLE 79
N-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5
triazin-2-amine
Part A: To 2,4-dichloro-6-methyl-s-triazine (Part A, Example 23,
2.0 grams, 12.3 mmol) in 50 mL of CH.sub.2 Cl.sub.2 chilled to 0
degrees was added morpholine (1.1 mL, 12.3 mmol) and the reaction
was allowed to come to room temperature and stirred for 2 hours.
The reaction was then poured into water and the layers separated.
The aqueous layer was washed with CH.sub.2 Cl.sub.2, (3.times.50
mL) and the organic layers were combined and dried. The solvent was
stripped and the crude material was chromatographed on silica with
30% ethyl acetate in hexane as the solvent to give
2-chloro-4-(N-morpholino)-6-methyl-s-triazine. C.sub.8 H.sub.11
N.sub.4 OCl (M+H).sup.+.
Part B: The product of Example 76; Part A (0.6 gram, 3.0 mmol) and
the product of Example 79; Part A (0.63 gram, 3.0 mmol) in dioxane
were stirred at room temperature for 24 hours. The reaction mixture
poured into water then extracted with ethyl acetate (3.times.50
mL). The extracts were dried with magnesium sulfate, filtered, and
concentrated in vacuo. The crude material was chromatographed on
silica using 30% ethyl acetate in hexanes as solvent to afford the
coupled material C.sub.14 H.sub.17 N.sub.6 O.sub.2 Br MS 381
(M+H).sup.+.
Part C: The product of part B above was alkylated in the same
manner as used in Example 5; part C to provide the title compound.
C.sub.16 H.sub.21 N.sub.6 O.sub.2 Br MS 409 (M+H).sup.+.
EXAMPLE 80
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylam
ino)carbonyl-6-methylpyrimidinamine
Sodium hydride (60% in oil, 0.1 g, 2.4 mmol), washed with hexanes
and decanted twice, was suspended in anhydrous
N,N-dimethylformamide (DMF) (5 mL) and a solution of
N-(2-bromo-.sup.4
-(1-methylethyl)phenyl)-N-ethyl-4-((2-furylmethyl)-amino)carbonyl-6-methyl
pyrimidinamine (1.0 g, 2.2. mmol) in anhydrous DMF (5 mL) was added
dropwise with stirring. After 30 min, iodomethane (0.37 g, 2.6
mmol) was added and the reaction mixture was stirred for 18 h.
Water (50 mL) was added carefully and the aqueous mix was extracted
three times with chloroform. The combined organic layers were dried
over MgSO.sub.4, filtered and concentrated in vacuo to give a brown
oil. Column chromatography (ethyl acetate:hexanes::1:2) afforded
the title product as a brown oil (850 mg, 82% yield, R.sub.f 0.35):
NMR (CDCl.sub.3 300 MHz): 7.5 (d, 1H, J=9), 7.3 (d, 1H, J=12),
7.25-7.2 (m, 1H), 7.12 (dd, 1H, J=8, 1), 6.8 (s, 1H), 6.3 (d, 1H,
J=12), 6.0 (br s, 0.5H), 5.9 (br s, 0.5H), 4.65 (br s, 2H), 4.2 (br
s, 1H), 3.75-3.6 (m, 1H), 3.0-2.8 (m, 4H), 2.4 (br s, 3H), 1.40 (d,
6H, J=7), 1.2 (t, 3H, J=8);
CI-HRMS: Calcd (C.sub.23 H.sub.27 BrN.sub.4 O.sub.2): 471.1396
(M+H); Found: 471.1387.
EXAMPLE 81
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino
)carbonyl)-6-methylpyrimidinamine
Sodium hydride (60% in oil, 0.12 g, 3 mmol), washed with hexanes
and decanted twice, was suspended in anhydrous THF (5 mL) and a
solution of 4-piperidone ethylene glycol ketal (0.43 g, 3 mmol) in
anhydrous THF (5 mL) was added dropwise with stirring. The reaction
mixture was heated to reflux temperature, stirred for 30 min and
then cooled to ambient temperature. A solution of methyl
2-((2-bromo-4-(1-methylethyl)-phenyl)ethylamino)-6-methyl-4-pyrimidinecarb
oxylate (Example 18) (1.0 g, 2.54 mmol) in anhydrous THF (10 mL)
was added and the reaction mixture was stirred at room temperature
for 98 h. The reaction mixture was poured onto a 1N NaOH solution
(100 mL), mixed and extracted three times with ethyl acetate and
the combined organic layers were dried over MgSO.sub.4, filtered
and concentrated in vacuo to give a brown oil. Column
chromatography (chloroform:methanol::9:1) afforded
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidin
o)carbonyl-6-methylpyrimidinamine as an orange-yellow oil (260 mg,
52% yield, R.sub.f 0.75):CI-HRMS: Calcd (C.sub.24 H.sub.31
BrN.sub.4 O.sub.3): 503.16578 (M+H); Found: 503.16571.
EXAMPLE 82
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-m
ethylpyrimidinamine
A solution-of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidin
o)carbonyl)-6-methylpyrimidinamine (260 mg) in a mixture of a 1N
HCl solution (2.5 mL) and THF (2.5 mL) was stirred at reflux
temperature for 20 h. The reaction mixture was poured into a 1N
NaOH solution, and extracted three times with ethyl acetate. The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to give the title product as a yellow oil
(240 mg, 100% yield, R.sub.f 0.75): NMR (CDCl.sub.3, 300 MHz): 7.5
(s, 1H), 7.2 (d, 1H, J=8), 7.1 (d, 1H, J=8), 6.8 (br s, 1H),
4.3-4.1 (m, 1H), 3.95-3.85 (m, 1H), 3.75-3.6 (m, 1H), 3.55-3.4 (m,
1H), 2.95-2.85 (m, 1H), 2.6-2.3 (m, 4H), 2.0-1.6 (m, 2H), 1.4-1.15
(m, 12H); CI-HRMS: Calcd (C.sub.22 H.sub.27 BrN.sub.4 O.sub.2):
459.1396 (M+H); Found: 459.1386.
EXAMPLE 83
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-met
hylpyriimidinamine, hydrochloride salt
A solution of borane in tetrahydrofuran (1M, 29 mL, 29 mmol) was
added dropwise to a solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidin
o)carbonyl-6-methylpyrimidinamine (1.67 g, 3.3 mmol) in anhydrous
THF (7 mL) with stirring under a nitrogen atmosphere. The reaction
mixture was heated to reflux temperature and stirred for 20 h, then
cooled to ambient temperature. A solution of glacial acetic acid
was added dropwise; then the reaction mixture was heated to reflux
temperature and stirred for 4 h, then cooled to ambient
temperature. The reaction mixture was concentrated in vacuo; the
residue was treated with excess 1N NaOH solution, and extracted
three times with ethyl acetate. The combined organic layers were
dried over MgSO.sub.4, filtered and concentrated in vacuo to give
an oil. Column chromatography (ethyl acetate) afforded
N-(2-bromo-4-(
1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)methyl-6-met
hylpyrimidinamine as a pale brown oil (860 mg): CI-MS, 489, 491
(M+H).
The ketal was dissolved in a mixture of a 33% HCl solution (10 mL)
and THF (5 mL). The resulting solution was stirred at reflux for 65
h, then cooled to ambient temperature and basified with a 1N NaOH
solution. The aqueous mix was extracted three times with ethyl
acetate. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to give an oil. Column
chromatography (ethyl acetate:hexanes::4:1) afforded the title
product as its free base and as an oil (600 mg, 41% overall yield):
CI-HRMS: Calcd (C.sub.22 H.sub.29 BrN.sub.4 O): 444.1603(M+H);
Found: 444.1594.
The above oil (0.55 g, 1.24 mmol) was dissolved in ether (5 mL) and
treated with a 1N HCl solution in ether. The resulting precipitate
was collected and washed with copious amounts of ether. Drying in
vacuo afforded a white powder (500 mg, 84% yield): mp
186-188.degree. C.; Anal.(C.sub.22 H.sub.29 BrN.sub.4 O-HCl): C,
54.92; H, 6.24; N, 11.65; Br, 16.64; Cl, 7.39; Found: C, 54.62; H,
6.37; N, 11.41; Br, 16.57; Cl, 7.35.
EXAMPLE 84
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methy
lpyrimidinamine
To a mixture of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimi
dinamine (1.57 g, 4.3 mmol), triethylamine(2.5 mL, 17 mmol) and
dichloromethane (15 mL) at 0.degree. C. under a nitrogen atmosphere
was added methanesulfonyl chloride (0.54 g, 4.7 mmol) dropwise and
the reaction mixture was stirred at 0.degree. C. for 1.5 h. It was
then washed successively with an ice-cold 1N HCl solution, a
saturated NaHCO.sub.3 solution and a saturated NaCl solution.
Drying the methylene chloride solution over MgSO.sub.4, filtration
and removal of solvent in vacuo gave
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methanesulfonyloxymethyl-6-m
ethylpyrimidinamine as a clear colorless oil (1.6 g): NMR
(CDCl.sub.3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.5 (s,
1H), 5.05-4.9 (br s, 2H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 1H),
3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.25 (br m, 3H), 1.3 (d,
6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 442, 444 (M+H).
To sodium hydride (60% in oil, 0.1 g, 2.4 mmol), washed with
hexanes and decanted twice, suspended in anhydrous THF (10 mL) was
added imidazole (146 mg, 2.14 mmol) in one portion and the reaction
mixture was warmed to reflux temperature and stirred for 2 h. A
solution of the crude mesylate in anhydrous THF (10 mL) was added
dropwise to the reaction mixture, which had been cooled to ambient
temperature. The reaction mixture was stirred for 68 h, then it was
poured onto water and extracted three times with ethyl acetate. The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to give an oil. Column chromatography (ethyl
acetate) afforded (1)
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimi
dinamine (130 mg, 8% overall yield, R.sub.f 0.7) and (2) the title
product (600 mg, 59% overall yield, R.sub.f 0.07): NMR (CDCl.sub.3,
300 MHz): 7.6-7.4 (m, 2H), 7.2 (dd, 1H, J=7, 1), 7.15 (d, 1H, J=8),
7.05 (s, 1H), 7.0-6.8 (m, 1H), 6.05 (s, 1H), 4.95-4.8 (m , 2H),
4.25-4.1 (m, 1H), 3.8-3.6 (m, 1H), 3.0-2.85 (m, 1H), 2.4-2.1 (br m,
3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-HRMS: Calcd (C.sub.20
H.sub.24 BrN5): 413.1293 (M+H), Found: 413.1275.
EXAMPLE 85
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymeth
yl)-6-methylpyrimidinamine
To a mixture of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimi
dinamine (1.0 g, 2.7 mmol), triethylamine (1.4 mL, 10 mmol) and
dichloromethane (20 mL) at 0.degree. C. under a nitrogen atmosphere
was added methanesulfonyl chloride (0.34 g, 3.0 mmol) dropwise. The
reaction was performed as for Example 84, except the reaction time
was 15 min.
Sodium hydride (0.12 g, 3 mmol) and 3-methoxybenzyl alcohol (0.41
g, 3 mmol) were reacted in anhydrous THF (10 mL) as for Example 84.
A solution of the crude mesylate in anhydrous THF (10 mL) was added
dropwise. The reaction mixture was stirred at reflux temperature
for 18 h, cooled to room temperature, poured into a 1N NaOH
solution and extracted three times with ethyl acetate. The combined
organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to give an oil. Column chromatography (ethyl
acetate:hexanes::1:1) afforded the title product as a viscous
yellow liquid (800 mg, 60% overall yield, R.sub.f 0.7): NMR
(CDCl.sub.3, 300 MHz): 7.5 (s, 1H), 7.3-7.1 (m, 4H), 6.95-6.9 (m,
2H), 6.85 (br d, 1H, J=8), 6.75 (s, 1H), 5.6 (br s, 2H), 4.45-4.3
(m, 2H), 4.25-4.05 (m, 1H), 3.8 (s, 3H), 3.8-3.6 (m, 1H), 2.9
(septet, 1H, J=7), 2.3 (br s, 3H), 1.3 (d, 6H, J=7), 1.2 (t, 3H,
J=7); CI-HRMS: Calcd (C.sub.25 H.sub.30 BrN.sub.3 O.sub.2):
484.1599; Found: 484.1592.
EXAMPLE 86
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methy
lpyrimidinamine
To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24
mmol) in anhydrous THF (5 mL) at -78.degree. C. under a nitrogen
atmosphere was added 2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol)
dropwise. After the addition was complete, the reaction mixture was
stirred at -78.degree. C. for 30 min. A solution of methyl
2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidin
ecarboxylate (Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10
mL) was added dropwise. The reaction mixture was then warmed to
-60.degree. C. and stirred for 4 h. A saturated aqueous solution of
NaHCO.sub.3 was added and the reaction mixture was warmed to
ambient temperature. Three extractions with ethyl acetate, followed
by two washings of the combined organic layers with water, drying
over MgSO.sub.4, filtration and concentration in vacuo gave a dark
brown oil. Column chromatography (ethyl acetate: hexanes::1:1)
afforded the title product, a brown solid (950 mg, 85% yield,
R.sub.f 0.43): mp 97-98.5.degree. C.; NMR (CDCl.sub.3, 300 MHz):8.0
(s, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H),
2.8-2.7 (m, 1H), 2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd:
445.0698 (M+H), Found: 445.0699; Anal.(C.sub.20 H.sub.21 BrN.sub.4
S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S, 7.21; Found: C,
53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.
EXAMPLE 87
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-meth
ylpyrimidinamine
To a solution of 1-(dimethylaminomethyl)imidazole (0.63 g, 5 mmol)
in anhydrous diethyl ether (50 mL) at -78.degree. C. under a
nitrogen atmosphere was added a solution of n-butyl lithium in
hexanes (2.4 M, 2.1 mL, 5 mmol) dropwise and the pale yellow
suspension was stirred at -78.degree. C. for 1 h. Methyl
2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidin
ecarboxylate (Example 18) (1.47 g, 5 mmol) was added in one portion
and the reaction mixture was warmed to room temperature over 23 h.
A 1N HCl solution was added until pH=1 (test paper) and the
reaction mixture was stirred for 4 h. A 3N NaOH solution was added
until the solution became basic (pH=10; test paper). Three
extractions with ethyl acetate, drying the combined organic layers
over MgSO.sub.4, filtration and concentration in vacuo gave a brown
oily solid. Column chromatography (chloroform:methanol::9:1)
afforded the title product, a yellow glass (900 mg, 42% yield,
R.sub.f 0.43): mp 75-76.degree. C.; NMR (CDCl.sub.3, 300 MHz):
12.2-12.1 (m, 1H), 7.7 (d, 1H, J=1), 7.45-7.35 (m, 2H), 7.3-7.2 (m,
2H), 6.55 (br s, 1H), 4.3 (sextet, 1H, J=7), 3.8 (sextet, 1H, J=7),
3.05 (septet, 1H, J=7), 2.65 (br s, 3H), 1.4 (d, 6H, J=7), 1.3 (t,
3H, J=7); CI-HRMS: Calcd: 428.1086 (M+H), Found: 428.1089; Anal
(C.sub.20 H.sub.24 BrN.sub.5 O) C, 56.08; H, 5.18; N, 16.35; Br,
18.66; Found: C, 56.20; H, 5.10; N, 15.88; Br, 18.73.
EXAMPLE 88
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylp
yrimidinamine
To a suspension of potassium hydride (35% in oil, 0.16 g, 1.4
mmol), washed with hexanes and decanted twice, in anhydrous ether
(5 mL), cooled to 0.degree. C. under a nitrogen atmosphere was
added a solution of 5-bromoindole (0.27 g, 1.4 mmol) in anhydrous
ether. After being stirred for 30 min., the reaction mixture was
cooled to -78.degree. C. and transferred via cannula to a
pre-cooled (-78.degree. C.) mixture of t-butyl lithium (1.7 M in
pentane, 1.6 mL, 2.7 mmol) in dry ether (5 mL). The resulting white
suspension was stirred at -78.degree. C. for 30 min and a solution
of methyl
2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidin
ecarboxylate (Example 18) (0.5 g, 1.25 mmol) in anhydrous ether (5
mL) was added dropwise. After quenching the reaction mixture as in
Example 87; it was extracted three times with ethyl acetate,
followed by two washings of the combined organic layers with a
saturated NaHCO.sub.3 solution, drying over MgSO.sub.4, filtration
and concentration in vacuo to give a dark brown oil. Column
chromatography (ethyl acetate: hexanes::1:4) afforded the title
product, a light brown solid (140 mg, 24% yield, R.sub.f 0.2): mp
77-79.degree. C.; NMR (DMSO-d.sub.6, 400 MHz, 90.degree. C.):
11.6-11.35 (br s, 1H), 8.30 (s, 1H), 7.75 (dd, 1H, J=8, 1), 7.55
(d, 1H, J=1), 7.4-7.35 (m, 2H), 7.35-7.25 (m, 2H), 6.9 (s, 1H),
6.60-6.55 (m, 1H), 4.1-3.7 (m, 2H), 2.95-2.8 (m, 1H), 2.4 (br s,
3H), 1.25-1.1 (m, 9H); Anal (C.sub.25 H.sub.25 BrN.sub.4 O): C,
62.90; H, 5.28; N, 11.74; Br, 16.74; Found: C, 63.13; H, 5.60; N,
11.37; Br, 16.80.
EXAMPLE 89
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-me
thylpyrimidinamine
To a suspension of N,O-dimethylhydroxylamine hydrochloride (1.46 g,
15 mmol) in benzene (20 mL) at 5-10.degree. C. under a nitrogen
atmosphere was added a solution of trimethyl aluminum in toluene (2
M, 7.5 mL, 15 mmol) dropwise and the reaction mixture was then
warmed to ambient temperature over 1 h. The reaction mixture was
transferred to an addition funnel and added dropwise to a solution
of methyl
2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)-6-methyl-4-pyrimidine
carboxylate (Example 18) (2.25 g, 5.73 mmol) in benzene (40 mL).
The reaction mixture was heated at reflux and stirred for 16 h.
After being cooled to room temperature, the mixture was poured into
a 5% HCl solution (100 mL), mixed and extracted three times with
ethyl acetate. The combined organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo to give a brown oil.
Column chromatography (ethyl acetate: hexanes::1:1) afforded
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-methyl-N-methoxycarboxami
do)-6-methylpyrimidinamine (1.0 g, 41% yield, R.sub.f 0.4): CI-MS,
421, 423 (M+H).
The crude amide was dissolved in anhydrous THF (10 mL). A solution
of 4-fluorophenylmagnesium bromide in ether (2 M, 1.25 mL, 2.5
mmol) was added dropwise and the reaction mixture was stirred for
22 h. The reaction was quenched by pouring onto a 1 N NaOH solution
(50 mL). The aqueous solution was extracted three times with ethyl
acetate. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to give an orange yellow oil.
Column chromatography (ethyl acetate:hexanes::1:9) afforded the
title product as a yellow solid (700 mg, 65% yield, R.sub.f 0.5):
mp 70.degree. C.; NMR (CDCl.sub.3, 300 MHz): 8.3-8.05 (m, 2H), 7.55
(d, 1H, J=1), 7.2-6.75 (m, 5H), 4.85-4.7 (m, 1H), 4.3-4.15 (m, 1H),
2.95 (septet, 1H, J=7), 2.5 (br s, 3H), 1.4-1.15 (m, 9H); CI-HRMS:
Calcd(C.sub.23 H.sub.23 BrFN.sub.3 O): 456.1087 (M+H), Found:
456.1084.
EXAMPLE 90
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyriimidinami
ne
A mixture of methyl
2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidin
ecarboxylate (Example 18) (10 g, 25 mmol), ethanol (100 mL) and a
1N NaOH solution (250 mL) was stirred at reflux temperature for 18
h. After being cooled to ambient temperature, the reaction mixture
was concentrated twofold in vacuo and acidified with a concentrated
HCl solution. Three extractions with chloroform, drying the
combined organic layers over MgSO.sub.4, filtration and removal of
solvent in vacuo gave a pale brown solid (9.0 g, 95% yield): mp
102-104.degree. C.; NMR (CDCl.sub.3, 300 MHz): 7.55 (d, 1H, J=1),
7.25-7.20 (m, 2H), 7.15 (d, 1H, J=7), 4.30-4.10 (m, 1H), 3.88-3.7
(m, 1H), 3.00-2.85 (m, 1H), 2.55 (br s, 3H), 2.30 (br s, 1H), 1.30
(d, 6H, J=7), 1.20 (t, 3H, J=7); CI-HRMS: Calcd(C.sub.17 H.sub.20
BrN.sub.3 O): 378.0817(M+H); Found: 378.0813.
EXAMPLE 91
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine
Cerium trichloride (4.9 g, 19.6 mmol) was dried, with magnetic
stirring, at 180.degree. C. in vacuo for 4 h. After being cooled to
room temperature and placed under a nitrogen atmosphere, the solid
was stirred for 16 h in anhydrous THF (50 mL).
A solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinami
ne (3.7 g, 9.8 mmol) in anhydrous THF (25 mL) was cooled with
stirring to -78.degree. C. under a nitrogen atmosphere. A solution
of methyl lithium in ether (1.4 M, 7 mL, 9.8 mmol) was added
dropwise and the reaction mixture was stirred at -78.degree. C. for
1 h. The CeCl.sub.3 suspension was transferred via cannula into the
reaction mixture and stirring at -78.degree. C. was continued for 5
h. A solution of methyl lithium in ether (1.4 M, 7 mL, 9.8 mmol)
was added dropwise and the reaction mixture was then warmed
gradually to room temperature over 16 h. After cooling the reaction
mixture to -78.degree. C., the reaction was quenched with a 1 N HCl
solution and warmed to room temperature. The resulting mixture was
extracted three times with ethyl acetate. The combined organic
layers were dried over MgSO.sub.4, filtered and concentrated in
vacuo to give an orange yellow oil. Column chromatography (ethyl
acetate:hexanes::1:4) afforded the title product as an oil (2.5 g,
68% yield, R.sub.f 0.5): NMR (CDCl.sub.3, 300 MHz): 7.55 (d, 1H,
J=1), 7.25-7.15 (m, 2H), 6.95 (s, 1H), 4.30-4.10 (m, 1H), 3.90-3.70
(m, 1H), 3.00-2.85 (m, 1H), 2.80-2.05 (m, 6H), 1.35-1.20 (m, 9H);
CI-HRMS: Calcd (C.sub.18 H.sub.22 BrN3O): 376.1024 (M+H), Found:
376.1042.
EXAMPLE 92
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-
methylpyrimidinamine (XU472)
Sodium borohydride (0.11 g, 2.8 mmol) was added to a solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6-methyl
pyrimidinamine (0.6 g, 1.4 mmol) in ethanol (5 mL). After being
stirred for 71 h, the reaction mixture was concentrated in vacuo,
treated with a 1 N NaOH solution and extracted three times with
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered and concentrated in vacuo to give a
colorless oil. Column chromatography (chloroform:methanol::9:1)
afforded the title product as an oil (600 mg, 96% yield, R.sub.f
0.4): NMR (CDCl.sub.3, 300 MHz): 8.65-8.45 (m, 2H), 7.55 (br s,
2H), 7.3-7.1 (m, 2H), 6.25-6.15 (m, 1H), 5.7-5.5 (m, 0.5H),
5.45-5.3 (m, 0.5H), 5.15-4.95 (m, 1H), 4.3-4.1 (m, 1H), 3.9-3.7 (m,
1H), 3.0-2.85 (m, 1H), 2.45-2.2 (m, 3H), 2.3-2.2 (m, 1H), 1.35-1.2
(m, 9H); CI-HRMS: Calcd (C.sub.22 H.sub.25 BrN4O): 441.1290 (M+H),
Found: 441.1274.
EXAMPLE 93
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-
hydroxymethyl)-6-methylpyrimidinamine
A solution of 4-bromoanisole (0.2 g, 1.1 mmol) in anhydrous THF (10
mL) was cooled with stirring to -78.degree. C. under a nitrogen
atmosphere. A solution of t-butyl lithium in pentane (1.7 M, 1.4
mL, 2.4 mmol) was added dropwise and the reaction mixture was
stirred for 0.5 h. A solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridyl-carbonyl)-6-methy
lpyrimidinamine (0.45 g, 1 mmol) in anhydrous THF (10 mL) was added
dropwise and the reaction mixture was warmed gradually to ambient
temperature over 18 h. The reaction mixture was poured onto a
saturated NH.sub.4 Cl solution and extracted three times with ethyl
acetate. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to give an oil. Column
chromatography (ethyl acetate:hexanes::4:1) afforded the title
product as a pale brown glass (170 mg, 31% yield, R.sub.f 0.2): mp
68-70.degree. C.; NMR (CDCl.sub.3, 300 MHz): 8.6-8.4 (m, 2H),
7.7-7.5 (m, 1H), 7.5 (s, 1H), 7.25-7.05 (m, 6H), 6.95-6.75 (m, 2H),
6.25-6.2 (m, 1H), 5.85-5.7 (m, 1H), 4.25-4.05 (m, 1H), 3.8 (br s,
3H), 3.95-3.75 (m, 1H), 3.00-2.8. (m, 1H), 2.45-2.1 (br s, 3H),
1.35-1.15 (m, 9H); CI-HRMS: Calcd(C.sub.29 H31BrN.sub.4 O.sub.2):
547.1709 (M+H), Found: 547.1709.
EXAMPLE 94
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyiimid
inamine, Hydrochloride Salt
Sodium (0.08 g, 3.5 mmol) was added to methanol (20 mL) with
stirring. After the sodium reacted, a solution of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinami
ne (1.0 g, 2.67 mmol) in methanol (5 mL) was added and the reaction
mixture was stirred for 5 min. Gold's reagent
((dimethylaminomethyleneaminomethylene))dimethyl-ammonium chloride
(0.66 g, 4 mmol) was added and stirring was continued for 19 h. The
reaction mixture was concentrated in vacuo; the residue was
dissolved in chloroform and the solution was washed with a
saturated NaHCO.sub.3 solution, dried over MgSO.sub.4 and filtered
solvent removal in vacuo gave a brown solid, which upon trituration
with hexanes afforded
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-dimethylaminopropenoyl)-6
-methylpyrimidinamine as a yellow solid (700 mg): NMR (CDCl.sub.3,
300 MHz): 7.9-7.65 (br s, 1H), 7.5 (s, 1H), 7.25-7.2 (m, 2H), 7.15
(s, 1H), 6.1-5.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.75 (m, 1H),
3.2-3.0 (br s, 3H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.3
(br s, 3H), 1.35-1.2 (m, 9H): CI-MS, 431, 433 (M+H).
A solution of the above vinylogous amide and anhydrous hydrazine
(0.15 g, 4.7 mmol) in toluene (15 mL) was stirred at reflux
temperature under a nitrogen atmosphere for 16 h. The reaction
mixture was poured onto water and extracted three times with ethyl
acetate. The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to give an oil. Column
chromatography (ether) afforded the free base of the title product
as a pale yellow glass (600 mg, 59% overall yield, R.sub.f 0.4):
NMR (CDCl.sub.3, 300 MHz): 7.6 (s, 1H), 7.55 (s, 1H), 7.3-7.2 (m,
2H), 6.8 (s, 1H), 6.75-6.6 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.7
(m, 1H), 3.00-2.85 (m, 1H), 2.5-2.2 (br s, 3H), 1.3 (d, 6H, J=8),
1.25 (t, 3H, J=8); CI-HRMS: Calcd (C.sub.19 H.sub.22 BrN.sub.5):
399.1137 (M+H), Found: 399.1140.
The free base was dissolved in ether and treated with an excess
amount of a 1 N HCl solution in ether. The resulting precipitate
was collected and washed with copious amounts of ether. Drying in
vacuo at 60.degree. C. afforded the title product as a powder (500
mg, 72% yield) mp 235-237.degree. C.; NMR (DMSO-d.sub.6, 300 MHz):
7.9-7.7 (m, 1H), 7.6 (s, 1H), 7.4-7.3 (m, 2H), 7.2 (s, 1H),
7.05-6.85 (m, 1H), 4.3-4.1 (m, 1H), 3.85-3.65 (m, 1H), 3.05-2.9 (m,
1H), 2.45-2.1 (br m, 3H), 1.25 (d, 6H, J=8), 1.2 (t, 3H, J=8);
Anal. (C.sub.19 H.sub.22 BrN.sub.5 -HCl): C, 52.75; H, 5.31; N,
16.03; Br, 18.29; Cl, 8.12; Found: C, 52.53; H, 5.28; N, 15.93; Br,
18.44; Cl, 8.17.
EXAMPLE 95
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimi
dinamine
A mixture of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinami
ne (0.5 g, 1.33 mmol), ammonium acetate (1.1 g, 14 mmol), sodium
cyanoborohydride (59 mg, 0.9 mmol) and methanol (5 mL) was stirred
at ambient temperature for 90 h. A concentrated HCl solution was
added until the solution became acidic (pH=2), then the reaction
mixture was concentrated in vacuo. The residue was taken up in
water, basified with a concentrated NaOH solution and extracted
three times with ether. The combined organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo to give an oil.
Column chromatography (ethyl acetate:hexanes:: 1: then
chloroform:methanol:NH.sub.4 OH::95:5:0.5) gave (1)
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminothyl)-6-methyl-pyrim
idinamine (80 mg, 16% yield, R.sub.f 0.34 (ethyl
acetate:hexanes::1;1)) and (2) the title product as a brown oil
(180 mg, 36% yield, R.sub.f 0.34 (chloroform:methanol:NH.sub.4
OH::95:5:0.5)): NMR (CDCl.sub.3, 300 MHz): 7.5 (d, 1H, J=1),
7.2-7.1 (m, 2H), 6.4 (s, 1H), 4.25-4.05 (m, 1H), 3.9-3.65 (m, 2H),
3.0-2.85 (m, 1H), 2.4-2.2 (br m, 3H), 1.9-1.6 (br m, 3H), 1.3 (d,
6H, J=8), 1.2 (t, 3H, J=8); CI-HRMS (C.sub.18 H.sub.25 BrN.sub.4):
377.1341 (M+H), Found: 377.1330.
EXAMPLE 96
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methyleth
yl)-6-methylpyrimidinamine
A mixture of
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyr
imidinamine (1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and
dichloromethane (15 mL) was stirred at 0.degree. C. under a
nitrogen atmosphere. Methanesulfonylchloride (364 mg, 3.2 mmol) was
added dropwise and the reaction mixture was then stirred for 1.5 h.
The resulting turbid solution was washed successively with an
ice-cold 1 N HCl solution, a saturated NaHCO.sub.3 solution and a
saturated NaCl solution. Drying over MgSO.sub.4, filtration and
removal of solvent in vacuo gave
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-
6-methylpyrimidinamine as a clear colorless oil (1.0 g): NMR
(CDCl.sub.3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.55 (s,
1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m, 1H), 3.0-2.5 (m, 4H), 2.5-2.05
(br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 456, 458
(M+H).
The crude mesylate was mixed with sodium cyanide (0.54 g, 11 mmol)
in N,N-dimethylformamide (DMF) (20 mL) and stirred at reflux
temperature for 67 h. After being cooled to room temperature, the
reaction mix was poured onto water (200 mL), mixed and extracted
with ethyl acetate three times. The combined organic layers were
dried over MgSO.sub.4, filtered and concentrated in vacuo to give
an oil. Column chromatography (ethyl acetate:hexanes::1:9) afforded
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-cyanoethyl)-6-methylpyrim
idinamine as an oil (440 mg, R.sub.f 0.24): NMR (CDCl.sub.3, 300
MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.65-6.55 (m, 1H),
4.3-4.05 (m, 1H), 3.9-3.5 (m, 2H), 3.0-2.85 (m, 1H), 2.55-2.0 (br
m, 3H), 1.8-1.4 (br m, 3H), 1.4-1.1 (m, 9H); CI-MS: 387, 389
(M+H).
A mixture of the crude cyanide, sodium azide (600 mg, 9 mmol),
ammonium chloride (492 mg, 9 mmol) and DMF (20 mL) was stirred at
100-105.degree. C. for 112 h. After being cooled to room
temperature, the reaction mixture was poured onto water (200 mL),
basified with a 1 N NaOH solution (pH>10) and extracted three
times with chloroform. The combined organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo to give an oil.
Column chromatography (chloroform:methanol::9:1) afforded a brown
solid (R.sub.f 0.22). Recrystallization from ether gave the title
product as a white solid (35 mg, 3% overall yield): mp
127-129.degree. C.; NMR (CDCl.sub.3, 400 MHz): 7.75 (s, 0.4H),
7.7(s, 0.6H), 7.45 (d, 0.6H, J=8), 7.4 (d, 0.4H, J=8), 7.3-7.2 (m,
2H), 6.5 (s, 0.4H), 6.48 (s, 0.6H), 4.28-4.0 (m, 1.4H), 4.28-4.18
(m, 0.6H), 3.94-3.82 (m, 0.6H), 3.8-3.7 (m, 0.4H), 3.1-3.0 (m, 1H),
2.45 (s, 3H), 1.5 (d, 3H, J=8), 1.4-1.3 (m. 5H), 1.3-1.2 (m, 4H);
CI-HRMS: 430.1355 (M+H); 430.1347.
EXAMPLE 97
2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine
A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47.0 g,
252 mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in
dioxane (400 mL) was stirred at reflux temperature for 20 h under a
nitrogen atmosphere. The reaction mixture was cooled to ambient
temperature and concentrated on a rotary evaporator. The residue
was treated with a saturated sodium bicarbonate solution and
extracted three times with ethyl acetate. The combined organic
layers were dried over magnesium sulfate and filtered. Solvent was
removed in vacuo to provide a red oil. Column chromatography (ethyl
acetate:hexanes::1:1) gave the title product as a crude oil.
Recrystallization from ether-hexanes, collection by filtration and
drying in vacuo afforded the title compound as a solid (42.8 g, 17%
yield): mp 75-76.degree. C.; NMR (CDCl.sub.3, 300 MHz): 8.4 (d, 1H,
J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H,
J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25
(d, 6H, J=7); Anal. (C.sub.16 H.sub.18 BrN.sub.3 O.sub.2): C,
52.76, H, 4.98; N, 11.54; Br, 21.94; Found: C, 52.71; H, 4.99; N,
11.38; Br, 21.83.
EXAMPLE 98
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)4-carbomethoxy-6-methylpyrim
idine
To sodium hydride (60% in oil, 4.8 g, 120 mmol), washed with
hexanes (50 mL) twice and decanted in anhydrous tetrahydrofuran
(150 mL) at ambient temperature under a nitrogen atmosphere was
stirred
2-(N-(2-bromo-4-(2-propyl)phenylamino)-4-carbomethoxy-6-methylpyrimidine
(42.8 g, 118 mmol) portionwise over 30 min. After gas evolution
subsided, iodoethane (31.2 g, 16 mL, 200 mmol) was added in one
portion and the reaction mixture was heated to a gentle reflux and
stirred for 24 h. After being cooled to room temperature, the
reaction mixture was quenched carefully with water and extracted
three times with ethyl acetate. The combined organic layers were
washed with water twice, dried over magnesium sulfate and filtered.
Solvent was removed in vacuo to afford a brown oil. Column
chromatography (ether:hexanes::1:1) provided two fractions: (1)
2-(N-(2-bromo-4-(2-propyl)phenylamino)-4-carbomethoxy-6-methylpyrimidine
(4.6 g, 11% yield, R.sub.f =0.8) and (2) the title product (20 g,
R.sub.f =0.7) as a crude oil.
The title product was recrystallized from hexanes and dried in
vacuo to give a solid (18.0 g, 39% yield): mp 81-82.degree. C.,
NMR(CDCl.sub.3, 300 MHz): 7.5 (br s, 1H), 7.25 (d, 1H, J=7), 7.15
(d, 1H, J=7), 7.1 (s, 1H), 4.3-4.1 (m, 1H), 4.05-3.75 (m, 4H), 2.95
(septet, 1H, J=7), 2.3 (br s, 3H), 1.3 (d, 6H, J=7), 1.25 (t, 3H,
J=7); CI-HRMS: calcd: 392.0974 (M+H), found: 392.0960.
EXAMPLE 99
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carbox
ylic acid, morpholine amide
To sodium hydride (60% in oil, 0.24 g, 6.0 mmol), washed with
hexanes twice and decanted, and suspended in anhydrous
tetrahydrofuran (10 mL) was added morpholine (0.52 g, 6.0 mmol) and
the reaction mixture was warmed to reflux temperature and stirred
for 1 h. The reaction mixture was then cooled to ambient
temperature and
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-py
rimidine (2.0 g, 5.1 mmol) was added and stirring was continued for
26 h. The reaction mixture was then poured onto a 1 N NaOH
solution, stirred and extracted three times with ethyl acetate. The
combined organic layers were dried over magnesium sulfate, filtered
and concentrated in vacuo. Column chromatography (ether) afforded
the title compound as a solid (900 mg, 39% yield): mp 145.degree.
C.; NMR (CDCl.sub.3, 300 MHz): 7.5 (d, 1H, J=1), 7.2 (dd, 1H,
J=7,1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3
(m, 11H), 3.1-3.0 (m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H, J=7),
1.15 (t, 3H, J=7); Anal. (C.sub.21 H.sub.27 BrN.sub.4 O.sub.2)
Calcd: C, 56.38; H, 6.08; N, 12.52; Br, 17.86; Found: C, 56.07; H,
6.05; N, 12.29; Br, 18.08.
EXAMPLE 100
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-(morpholinomethyl)-6-meth
ylpyrimidine
To a solution of
2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carbo
xylic acid, morpholine amide (750 mg, 1.72 mmol) in anhydrous
tetrahydrofuran (1.4 mL) at ambient temperature under a nitrogen
atmosphere was added a solution of borane in tetrahydrofuran (1 M,
3.6 mL, 3.6 mmol) dropwise and the reaction mixture was heated at
reflux temperature for 20 h. After cooling to room, acetic acid
(3.5 mL) was slowly added and the mixture was heated at reflux for
30 min. After being cooled to ambient temperature, the reaction
mixture was poured into a 3 N NaOH solution and extracted three
times with ethyl acetate. The combined organic layers were dried
over magnesium sulfate, filtered and concentrated in vacuo. Column
chromatography (ethyl acetate) afforded the title compound as an
oil (300 mg, 39% yield, R.sub.f 0.3): NMR (CDCl.sub.3, 300 MHz) 7.5
(s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 (s, 1H), 4.3-4.1
(m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H), 2.9 (septet, 1H, J=7),
2.55-2.35 (br m, 3H), 2.35-2.25 (m, 2H), 1.3 (d, 6H, J=7), 1.2 (t,
3H, J=7); CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.
EXAMPLE 101
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chlropurine
Part A: Fuming nitric acid (40 mL) was added in portions to
4,6-dihydroxy-2-methylpyrimidine while cooling the reaction flask
on ice. After completion of addition, the reaction was stirred an
additional 60 min over ice followed by another 60 min at room
temperature. The reaction mixture was then poured over ice (60 g)
and the ice allowed to melt. A light pink solid was isolated by
filtration and washed with cold water (50 mL). The solid was dried
in a vacuum oven overnight to yield 22.6 g of product.
Part B: The product of Part A was added portionwise to phosphorus
oxychloride (125 mL) under a nitrogen atmosphere.
N,N-diethylaniline (25 mL) was added portionwise and the reaction
mixture was refluxed for 150 min. then cooled to room temperature.
The reaction mixture was poured over ice (750 g) and stirred for 1
hr. The aqueous layer was extracted with diethyl ether (4.times.400
mL) and the extracts combined. The extracts were washed with brine
(300 mL) and the organic layer dried over Na.sub.2 SO.sub.4. The
dried organic layer was filtered and stripped down to a tan solid
(21.51 g).
Part C: The product of Part B (3.0 g) was added to acetic acid (5.5
mL) and methanol (25 mL). This solution was added to iron powder
(3.0 g) and the reaction was stirred for two hrs at 60-65.degree.
C. The reaction was cooled to room temperature and the product was
filtered. The filtrate was stripped to a brown solid, which was
extracted with ethyl acetate (3.times.100 mL). The combined organic
extracts were washed with NaOH (1 N, 2.times.100 mL), water (100
mL), and brine (100 mL). The organic layer was dried over Na.sub.2
SO.sub.4, filtered, and stripped to yield (2.13 g) an amber liquid
that solidified upon cooling. MS (M+H).sup.+ 178.
Part D: The product of Part C (2.0 g), 2-bromo-4-isopropylaniline
(2.4 g), and diisopropylethylamine (1.52 g) were mixed and the
reaction mass was heated to 160.degree. C. for 25 min. Purification
of the reaction mass by flash chromatography (CH.sub.2 Cl.sub.2
:MeOH, 50:1; silica) followed by stripping of the
product-containing fractions yielded (1.45 g) an off white solid.
MS (M+H).sup.+ 356.
Part E: The product of Part D (1.32 g), triethylorthoformate (10
mL), and acetic anhydride (10 mL) were mixed under nitrogen and
refluxed for 4.5 hrs. The reaction mixture was reduced to an oil
and water (50 mL) was added. The aqueous mixture was basified (pH
8) with solid Na.sub.2 CO.sub.3 and extracted with CHCl.sub.3
(3.times.80 mL). The combined organic extracts were dried over
Na.sub.2 SO.sub.4, filtered and stripped to yield an amber oil
(1.63 g). Purification by flash chromatography (CH.sub.2 Cl.sub.2
:MeOH, 50:1; silica) yielded a light amber glass
9[2-bromo-4(2-propyl )phenyl]-2-methyl-6-chloropurine (0.94 g). Mp
49-52.degree. C. MS (M+H).sup.+ 367.
EXAMPLE 102
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-morpholinopurine
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (1.3 g) and
morpholine (10 mL) were combined under nitrogen and refluxed for 6
hrs. The reaction mixture was concentrated by rotovap and the
residue was purified by flash chromatography (CH.sub.2 C.sub.2
:MeOH, 50:1; silica) to yield a yellow solid (0.54 g). MS
(M+H).sup.+ 416, 418.
EXAMPLE 103
9[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine
Part A: Fuming nitric acid (40 mL) was added in portions to
4,6-dihydroxy-2-methylpyrimidine while cooling the reaction flask
on ice. After completion of addition, the reaction was stirred an
additional 60 min over ice followed by another 60 min at room
temperature. The reaction mass was then poured over ice (60 g) and
the ice allowed to melt. A light pink solid was isolated by
filtration and washed with cold water (50 mL). The solid was dried
in a vacuum oven overnight to yield 22.6 g of product.
Part B: The product of Part A was added portionwise to phosphorus
oxychloride (125 mL) under a nitrogen atmosphere and
N,N-diethylaniline (25 mL) was added portionwise. The reaction
mixture was refluxed for 150 min, cooled to room temperature,
poured over ice (750 g) and stirred for 1 hr. The aqueous layer was
extracted with diethyl ether (4.times.400 mL) and the extracts
combined. The extracts were washed with brine (300 mL), dried over
Na.sub.2 SO.sub.4, filtered, and stripped down to a tan solid
(21.51 g).
Part C: The product of Part B (6.5 g) was added to acetic acid (11
mL) and methanol (50 mL). This solution was added to iron powder
(6.0 g), stirred for two hrs at 60-65.degree. C., cooled to room
temperature, and filtered. The filtrate was stripped to a brown
solid, which was extracted with ethyl acetate (3.times.100 mL). The
combined organic extracts were washed with NaOH (1 N, 2.times.100
mL), water (100 mL), and brine (100 mL). The organic layer was
dried over Na.sub.2 SO.sub.4, filtered, and stripped to yield (4.75
g) an amber liquid that solidified upon cooling. MS (M+H).sup.+
178.
Part D: The product of Part C (4.75 g) and
2-bromo-4-isopropylaniline (5.71 g) were mixed and the reaction
mass heated to 140.degree. C. for 60 min. The reaction mass was
suspended in CH.sub.2 Cl.sub.2 (300 mL) and the organic solution
was washed with NaOH (1 N, 3.times.250 mL) and brine (250 mL). The
organic phase was dried over Na.sub.2 SO.sub.4, and stripped to a
dark liquid (9.28 g). The liquid was purified by flash
chromatography (CH.sub.2 Cl.sub.2 :MeOH, 50:1; silica) to yield
(6.27 g) a light red solid. MS (M+H).sup.+ 356.
Part E: The product of Part D (2.0 g) was added to acetic acid
(50%, 20 mL) and sodium nitrite (0.407 g) in water (2.0 mL) was
added dropwise at room temperature. After 4.25 hrs, the reaction
mixture was filtered and the collected solid was purified by flash
chromatography (CH.sub.2 Cl.sub.2 :MeOH, 50:1; silica) to yield an
orange oil 9
[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine (0.75 g).
MS (M+H).sup.+ 368.
EXAMPLE 104
9[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-morpholinopurine
9 [2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine (1.34g)
and morpholine (10 mL) were combined under nitrogen and refluxed
for 2.5 hrs. CH.sub.2 Cl.sub.2 (200 mL) was added to the reaction
mixture and the resulting solution washed with water (2.times.100
mL) and brine (100 mL). The organic phase was dried over Na.sub.2
SO.sub.4, concentrated by rotovap and the residue purified by flash
chromatography (CH.sub.2 Cl.sub.2, silica) to yield a yellow solid
(0.62 g). MP 145-148.degree. C. MS (M+H).sup.+ 417, 419.
EXAMPLE 105
2-(N-(2,4-dimethyoxypyrimidin-5-yl)-N-ethylamino)-4,6dimethylpyrimidine
Part A: 5-Nitrouracil (25 g) was added to phosphorus oxychloride
(130 mL) and N,N-diethylamine (32 mL) and the reaction was heated
to reflux for 70 min. under nitrogen. After cooling to room
temperature, the reaction mixture was poured over ice (600 g) and
the mixture stirred until it reached room temperature (60 min). The
aqueous layer was extracted with diethyl ether (4.times.300 mL).
The extracts were combined, washed with brine (200 mL), and dried
over Na.sub.2 SO.sub.4. The organic layer was then stripped to
yield an orange red liquid (17.69 g).
Part B: The product of Part A (17.69 g) in 60 mL methanol was added
dropwise to a solution of sodium methoxide (30% wt, 38 mL) while
cooling the flask in an ice bath. After addition was complete, the
reaction mixture was stirred overnight at room temperature and then
refluxed for 4 hrs. After cooling to room temperature, the reaction
mixture was poured over ice (500 g) and the white precipitate that
formed (10.38 g) was collected by filtration.
Part C: The product of Part B (4.1 g) and Pd/C (10% wt, 0.15 g)
were added to ethanol (70 mL), methanol (10 mL) and water (1 mL) in
a Parr reactor. The reaction mass was treated with hydrogen until
TLC analysis showed no starting material. The reaction mass was
filtered through celite and the filtrate stripped yielding a tan
solid (3.32 g).
Part D: The product of Part C (1.086 g) and
2-chloro-4,6-dimethyl-pyrimidine (1.0 g) were dissolved in THF (50
mL) under nitrogen. Sodium hydride (0.336 g, 60% wt dispersion in
oil) was added portionwise. After addition, the reaction was
refluxed for 5.5 hrs, cooled to room temperature and the solid
removed by filtration. The filtrate was concentrated and purified
by flash chromatography (CH.sub.2 C.sub.2 :MeOH, 90:10, silica) to
give a solid (0.52 g). MS (M+H).sup.+ 262.
Part E: The product of Part D (2.0 g) and iodoethane (1.49 g) were
dissolved in dimethylformamide (20 mL) under nitrogen. Sodium
hydride (0.383 g, 60% wt dispersion in oil) was added portionwise.
After addition, stirring was continued at room temperature for 22
hrs. Water (200 mL) was added and the mixture was extracted with
ethyl acetate (3.times.200 mL). The combined extracts were washed
with water (100 mL) and brine (100 mL), dried over Na.sub.2
SO.sub.4, filtered, and stripped to give an amber liquid
2-(N-(2,4-dimethyoxypyrimidin-5-yl)-N-ethylamino)-4,6-dimethylpyrimidine
(2.68 g). MS (M+H)+290.
Many of the compounds described above may be converted to their
salts by addition of the corresponding acid in a solution of the
compound in an organic solvent. The choice of addition salt
described above is not intended to limit the invention, and is
intended to be illustrative of the generality of the described
syntheses. Physical properties of representative compounds that can
be synthesized utilizing the methods described above are provided
in the tables below (Table 1 through Table 17). The column in the
tables headed "Synth. Ex." refers to the synthesis examples 1-105;
supra. The designations "MS" and "HRMS" refer to low and high
resolution mass spectral data, respectively.
TABLE 1 ##STR46## Synth. Ex. Ex. R.sup.1 R.sup.3 R.sup.4 X, X'
R.sup.5 mp, .degree. C. 1* 1 CH.sub.3 CH.sub.3 CH.sub.3 Br, H
CH.sub.3 120-121 2* CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 O, H
CH.sub.3 O 112-113 3* CH.sub.3 CH.sub.3 allyl Br, H H 127-129 4* 2
CH.sub.3 CH.sub.3 CH.sub.3 Br, H iC.sub.3 H.sub.7 163-164 5
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H H 94-95 6 CH.sub.3
morpholino CH.sub.3 Br, H CH.sub.3 40-42 7 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 CH.sub.3 O, H CH.sub.3 O 120-121 8 CH.sub.3
CH.sub.3 CH.sub.3 Br, H Br 101-103 9* 3 CH.sub.3 CH.sub.3 CH.sub.3
Br, H C.sub.2 H.sub.5 126-127 10* CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
Br, H tC.sub.4 H.sub.9 191-193 11* CH.sub.3 CH.sub.3 CH.sub.3 Br, H
tC.sub.4 H.sub.9 193-195 12 CH.sub.3 CH.sub.3 CH.sub.3 Br, H
CF.sub.3 106-107 13* CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
CF.sub.3 125-130 14 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 O, CH.sub.3
O 145-146 CH.sub.3 O 15 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3
O, CH.sub.3 O 115-116 CH.sub.3 O 16* 4 CH.sub.3 morpholino C.sub.2
H.sub.5 Br, H iC.sub.3 H.sub.7 219-222 17* CH.sub.3 morpholino
allyl Br, H iC.sub.3 H.sub.7 208-211 18* CH.sub.3 CH.sub.3 allyl
Br, H nC.sub.4 H.sub.9 116-118 19* CH.sub.3 CH.sub.3 C.sub.2
H.sub.5 Br, H nC.sub.4 H.sub.9 124-126 20 CH.sub.3 CH.sub.3
nC.sub.3 H.sub.7 Br, H nC.sub.4 H.sub.9 49-50 21* 5 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 151-153 22*
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H cC.sub.6 H.sub.11 170-172
23* C.sub.2 H.sub.5 C.sub.2 H.sub.5 C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 120-121 24* C.sub.2 H.sub.5 C.sub.2 H.sub.5 C.sub.2 H.sub.5
Br, H nC.sub.4 H.sub.9 116-118 25 CH.sub.3 4-CHO-piperazino C.sub.2
H.sub.5 Br, H iC.sub.3 H.sub.7 61-63 26* CH.sub.3 CH.sub.3 allyl
Br, H iC.sub.3 H.sub.7 141-142 27* CH.sub.3 CH.sub.3 C.sub.2
H.sub.5 I, H iC.sub.3 H.sub.7 149-150 28 CH.sub.3 CF.sub.3 C.sub.2
H.sub.5 Br, H iC.sub.3 H.sub.7 liquid 29* 6 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 Br, H C.sub.2 H.sub.4 --OCH.sub.3 117-119 30 7
CH.sub.3 4-morpholino C.sub.2 H.sub.5 I, H iC.sub.3 H.sub.7 96-98
31* 8 CH.sub.3 2-thiopheno C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7
95-97 32 CH.sub.3 CH.sub.3 CH.sub.2 CN Br, H iC.sub.3 H.sub.7 33* 9
CH.sub.3 CH.sub.3 CH.sub.2 cyclopropyl Br, H iC.sub.3 H.sub.7
146-148 34 10 CH.sub.3 CH.sub.3 propargyl Br, H iC.sub.3 H.sub.7 MS
35 11 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H C.sub.2 H.sub.4
--OCH.sub.3 36 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H CH.sub.2
--OCH.sub.3 37* CH.sub.3 4-allyloxy-piperidin-1-yl C.sub.2 H.sub.5
Br, H iC.sub.3 H.sub.7 38 CH.sub.3 morpholino C.sub.2 H.sub.5 I, H
CH.sub.2 --OCH.sub.3 39 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3
S, H CH.sub.2 --OCH.sub.3 40 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
(CH.sub.3).sub.2 N, CH.sub.2 --OCH.sub.3 H 41 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 CH.sub.3 S, H iC.sub.3 H.sub.7 42 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 (CH.sub.3).sub.2 N, iC.sub.3 H.sub.7 H 43 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 S, H CH.sub.3 S 44 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 S, H CH.sub.2 --SCH.sub.3 45
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, Br iC.sub.3 H.sub.7 46
CH.sub.3 thiomorpholino C.sub.2 H.sub.5 Br, Br iC.sub.3 H.sub.7 47
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H I 48 CH.sub.3 morpholino
C.sub.2 H.sub.5 I, H I 49* 12 H CH.sub.3 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 145-147 50 13 CH.sub.3 N(CH.sub.3)CH.sub.2
--CH.sub.2 OH C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 HRMS 51*
CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.3 CH.sub.3 O, CH.sub.3 CH.sub.3 O
52* CH.sub.3 CH.sub.3 CH.sub.3 H, H I 175-177 53* CH.sub.3 CH.sub.3
CH.sub.3 I, H H 164-166 54* CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3, H
H 55* CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.3 Br, H C.sub.2 H.sub.4
--OCH.sub.2 CH.sub.3 127-129 56 14 CH.sub.3 thiomorpholino-S-oxide
C.sub.2 H.sub.5 I, H iC.sub.3 H.sub.7 52-55 57* 15 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 Br, H O--iC.sub.3 H.sub.7 MS 58 16
CH.sub.3 C(.dbd.O)-4-morpholino C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 145 59 17 CH.sub.3 CH.sub.2 -4-morpholino C.sub.2 H.sub.5
Br, H iC.sub.3 H.sub.7 liquid 60 CH.sub.3 C(.dbd.O)-1-piperidinyl
C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 107-108 61 18 CH.sub.3
C(.dbd.O)OCH.sub.3 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 81-82 62
CH.sub.3 C(.dbd.O)NH-cyclohexyl C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 115 63 19 CH.sub.3 C(.dbd.O)-4-methyl)-1-piperazinyl
C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 81-82 64 20 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 Br, H CH.sub.2 --CH.sub.2 OH 58-60 65* 21
CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3, H CH.sub.3 66* CH.sub.3
CH.sub.3 CH.sub.3 H, H iC.sub.3 H.sub.7 67 CF.sub.3 CH.sub.3
C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 68* CH.sub.3 CH.sub.3
CH.sub.3 H, H I 175-177 69* CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3, H
H 70* CH.sub.3 CH.sub.3 CH.sub.2 CN Br, H iC.sub.3 H.sub.7 71*
CH.sub.3 CH.sub.3 CH.sub.3 Br, H H 72* CH.sub.3
(2-methoxymethyl)-1-pyrrolyl CH.sub.3 Br, H H 73 22 CH.sub.3
4-thiomorpholino C.sub.2 H.sub.5 I, H iC.sub.3 H.sub.7 51-53 73* 22
CH.sub.3 4-thiomorpholino C.sub.2 H.sub.5 I, H iC.sub.3 H.sub.7
234-236 74 CH.sub.3 4-hydroxy-1-piperidinyl C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 61-63 138 24 CH.sub.3 CH.sub.2 OH CH.sub.3 Br, H
iC.sub.3 H.sub.7 oil, MS 139 25 CH.sub.3 CH.sub.2 OCH.sub.3
CH.sub.3 Br, H iC.sub.3 H.sub.7 oil, MS 140 26 CH.sub.3 SCH.sub.3
C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS 141 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 O, Cl CH.sub.3 O 99-102 142
CH.sub.3 ##STR47## C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 78-81
143* CH.sub.3 ##STR48## C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7
131-135 144* CH.sub.3 ##STR49## C.sub.2H.sub.5 Br, H iC.sub.3
H.sub.7 98-102 145 CH.sub.3 CH.sub.3 H CH.sub.3 O, Cl CH.sub.3 O
170-173 146* CH.sub.3 NHNH.sub.2 C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 117-121 147 CH.sub.3 ##STR50## C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 148 CH.sub.3 ##STR51## C.sub.2 H.sub.5 Br,
H iC.sub.3 H.sub.7 oil, MS 149 CH.sub.3 OCH.sub.2 Ph C.sub.2
H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS 150 CH.sub.3
O(CH.sub.2).sub.3 SCH.sub.3 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7
oil, MS 152 CH.sub.3 ##STR52## C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 oil, MS 153 CH.sub.3 ##STR53## C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 154 CH.sub.3 Cl C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 155 CH.sub.3 NH.sub.2 C.sub.2 H.sub.5 Br,
H iC.sub.3 H.sub.7 oil, MS 156 CH.sub.3 O(CH.sub.2).sub.3 SO.sub.2
CH.sub.3 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS 157
CH.sub.3 ##STR54## C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS
158 CH.sub.3 ##STR55## C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil,
MS 159 27 CH.sub.3 SO.sub.2 CH.sub.3 C.sub.2 H.sub.5 Br, H iC.sub.3
H.sub.7 oil, MS 160 28 CH.sub.3 SOCH.sub.3 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 161* CH.sub.3 O(CH.sub.2).sub.2
N(CH.sub.3).sub.2 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 143-146
162 CH.sub.3 O(CH.sub.2).sub.3 SOCH.sub.3 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 163 CH.sub.3 NH(CH.sub.2).sub.2
N(CH.sub.3).sub.2 C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS
164 CH.sub.3 NH(CH.sub.2).sub.4 NH.sub.2 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 oil, MS 165 31 CH.sub.3 morpholino allyl I, H
iC.sub.3 H.sub.7 109-112 166 34 CH.sub.3 thiomorpholino H Br, Br
iC.sub.3 H.sub.7 194-195 167 32 CH.sub.3 Cl C.sub.2 H.sub.5 I, H
iC.sub.3 H.sub.7 liquid 168 35 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
SCH.sub.3, H iC.sub.3 H.sub.7 64-66 169 37 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 S(O)CH.sub.3, iC.sub.3 H.sub.7 144-146 H 170* 36
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H iC.sub.3 H.sub.7
141-142 171 38 CH.sub.3 thiazolidino C.sub.2 H.sub.5 I, H iC.sub.3
H.sub.7 liquid 172 39 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H
CH.sub.3 OCH.sub.2 liquid 173* 40 CH.sub.3 CH.sub.3 C.sub.3 H.sub.6
S--, H iC.sub.3 H.sub.7 157-159 174 41 CH.sub.3 CH.sub.3 C.sub.2
H.sub.5 S(O).sub.2 CH.sub.3, iC.sub.3 H.sub.7 174-176 H 175* 42
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SC.sub.2 H.sub.5, H iC.sub.3
H.sub.7 128-130 176 43 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SC.sub.2
H.sub.5, H CH.sub.3 CNO--CH.sub.3 77-78 177 33 CH.sub.3 N-methyl
prolinol C.sub.2 H.sub.5 SCH.sub.3, H iC.sub.3 H.sub.7 101-103 178
44 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H CH.sub.3
CNO--CH.sub.3 106-108 179 45 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
S(O).sub.2 CH.sub.3, CH.sub.3 CNO--CH.sub.3 151-154
H 180 46 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H Br 91-93
181 47 CH.sub.3 CH.sub.3 iC.sub.3 H.sub.7 SCH.sub.3, H C.sub.2
H.sub.5 85-87 182* 48 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3,
H C.sub.2 H.sub.5 140-141 183 49 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
SCH.sub.3, H CH.sub.3 NCO--CH.sub.3 158-160 184 50 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H CO.sub.2 C.sub.2 H.sub.5
99-100 185 51 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H
OCH.sub.3 128-130 186 52 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
SCH.sub.3, H CN 99-100 187 53 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
SCH.sub.3, H COCH.sub.3 125-126 188 54 CH.sub.3 CH.sub.3 C.sub.2
H.sub.5 SCH.sub.3, H COC.sub.2 H.sub.5 139-141 189 55 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H CH(OCH.sub.3)CH.sub.3 liquid
190 56 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H NHCH.sub.3
141-142 191 57 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 SCH.sub.3, H
N(CH.sub.3).sub.2 119-120 192 CH.sub.3 pyrrolidino C.sub.2 H.sub.5
Br, H iC.sub.3 H.sub.7 106-107 193 CH.sub.3 pyrrolidino CH.sub.3
Br, H iC.sub.3 H.sub.7 119-120 194 C.sub.2 H.sub.5 piperidino
CH.sub.3 Br, H iC.sub.3 H.sub.7 211-212 195 CH.sub.3 piperidino
CH.sub.3 Br, H iC.sub.3 H.sub.7 186-187 196 CH.sub.3 CH.sub.3
C.sub.3 H.sub.7 Br, H iC.sub.3 H.sub.7 150-151 197 CH.sub.3
CH.sub.3 C.sub.4 H.sub.9 Br, H iC.sub.3 H.sub.7 159-160 198
CH.sub.3 CH.sub.3 N,N-diethylacetamidino Br, H iC.sub.3 H.sub.7
101-102 199 CH.sub.3 CH.sub.3 N,N-diethylaminoethyl Br, H iC.sub.3
H.sub.7 65-66 200 CH.sub.3 CH.sub.3 N,N-dimethylaminoethyl Br, H
iC.sub.3 H.sub.7 118-120 201 CH.sub.3 CH.sub.3 Et Br, H OEt HRMS
202 CH.sub.3 CH.sub.3 Et Br, OMe OMe 113-115 203 CH.sub.3 CH.sub.3
H Br, OMe OMe 177-179 204 CH.sub.3 CH.sub.3 H Br, H OMe 118-119 205
CH.sub.3 CH.sub.3 Allyl Br, OMe OMe 88-90 206 CH.sub.3 CH.sub.3 Et
Br, H OMe HRMS 207 CH.sub.3 CH.sub.2 OCH.sub.3 Et I, H iC.sub.3
H.sub.7 HRMS 208 CH.sub.3 CH.sub.2 O(4-methoxyphenyl) Et Br, H
iC.sub.3 H.sub.7 HRMS 209 CH.sub.3 CH.sub.2 OPh Et Br, H iC.sub.3
H.sub.7 HRMS 210 CH.sub.3 CH.sub.2 O(2-pyridyl) Et Br, H iC.sub.3
H.sub.7 HRMS 211 CH.sub.3 CH.sub.2 OCH.sub.2 (4-methyl benzoate) Et
Br, H iC.sub.3 H.sub.7 HRMS 212 CH.sub.3 CH.sub.2 OCH.sub.2
(3,4,5-trimethoxyphenyl) Et Br, H iC.sub.3 H.sub.7 HRMS 213
CH.sub.3 CH.sub.2 O(2-pyrimidinyl) Et Br, H iC.sub.3 H.sub.7 HRMS
214 CH.sub.3 CH.sub.2 O(3,4,5-trimethoxyphenyl) Et Br, H iC.sub.3
H.sub.7 HRMS 215 CH.sub.3 CH.sub.2 O(3-(N,N-dimethyl)anilino) Et
Br, H iC.sub.3 H.sub.7 HRMS 216 CH.sub.3 CH.sub.2 OCH.sub.2
(3-pyridyl) Et Br, H iC.sub.3 H.sub.7 HRMS 217 CH.sub.3 CH.sub.2
O(4-methyl benzoate) Et Br, H iC.sub.3 H.sub.7 136-139 218 CH.sub.3
CH.sub.2 O(4-(1-imidazole)phenyl) Et Br, H iC.sub.3 H.sub.7 HRMS
219 CH.sub.3 CH.sub.2 OCH.sub.2 (4-pyridyl) Et Br, H iC.sub.3
H.sub.7 HRMS 220 CH.sub.3 CH.sub.2 OCH.sub.3 Et Br, H iC.sub.3
H.sub.7 221 CH.sub.3 CH.sub.2 OCH.sub.2 (2-furyl) Et Br, H iC.sub.3
H.sub.7 HRMS 222 58 CH.sub.3 CHO Et Br, H iC.sub.3 H.sub.7 HRMS 223
CH.sub.3 CH.sub.3 H Br, Br OMe 175-177 224 63 CH.sub.3 CH.sub.3 Et
Br, Br OEt 107-108 225 59 CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 OH
Et Br, H iC.sub.3 H.sub.7 HRMS 226 CH.sub.3 CH.sub.3 Et Br, Br OMe
101-103 227 CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 Et Br, H
iC.sub.3 H.sub.7 HRMS 228 CH.sub.3 CH.sub.3 H Br, Br OEt 165-167
229 CH.sub.3 CH.sub.2 OCH.sub.2 CO(4-morpholino) Et Br, H iC.sub.3
H.sub.7 HRMS 230 60 CH.sub.3 CH.sub.3 Et Br, OH OMe 157-160 231
CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 (4-morpholino) Et Br, H
iC.sub.3 H.sub.7 HRMS 268 CH.sub.3
(4-(2-methoxyphenyl)piperazinyl)carbonyl Et Br, H iC.sub.3 H.sub.7
57-60 269 CH.sub.3 (1,2,3,4-tetrahydroquinolinyl)carbonyl Et Br, H
iC.sub.3 H.sub.7 143-145 270 CH.sub.3 (2-furylmethyl)aminocarbonyl
Et Br, H iC.sub.3 H.sub.7 87-88 271 CH.sub.3 MeNHCO Et Br, H
iC.sub.3 H.sub.7 oil, MS 272 CH.sub.3
(4-(pyrazinyl)piperazino)carbonyl Et Br, H iC.sub.3 H.sub.7 51-53
273 CH.sub.3 (4-(2-pyrimidyl)piperazino)carbonyl Et Br, H iC.sub.3
H.sub.7 114-116 274 CH.sub.3 (4-(2-pyridyl)piperazino)carbonyl Et
Br, H iC.sub.3 H.sub.7 oil, MS 275 CH.sub.3
(4-(2-methoxyphenyl)piperazinyl)methyl, HCl salt Et Br, H iC.sub.3
H.sub.7 102-104 276 CH.sub.3 N-(2-furylmethyl)-N-methylaminomethyl
Et Br, H iC.sub.3 H.sub.7 oil, MS 277 CH.sub.3
(1,2,3,4-tetrahydroquinolinyl)methyl, HCl salt Et Br, H iC.sub.3
H.sub.7 88-90 278 CH.sub.3 (4-pyrazinylpiperazino)methyl Et Br, H
iC.sub.3 H.sub.7 oil, MS 279 CH.sub.3 dimethylaminomethyl Et Br, H
iC.sub.3 H.sub.7 oil, MS 280 CH.sub.3
(4-(2-pyridyl)piperazino)methyl, HCl salt Et Br, H iC.sub.3 H.sub.7
117-119 281 CH.sub.3 (4-(2-pyrimidyl)piperazino)methyl, HCl salt Et
Br, H iC.sub.3 H.sub.7 125-127 282 CH.sub.3 Me.sub.2 NCO Et Br, H
iC.sub.3 H.sub.7 80-82 283 CH.sub.3 3-indoylcarbonyl, HCL salt Et
Br, H iC.sub.3 H.sub.7 105-107 284 CH.sub.3 3-pyridylcarbonyl Et
Br, H iC.sub.3 H.sub.7 165-167 285 CH.sub.3 3-phenylcarbonyl Et Br,
H iC.sub.3 H.sub.7 oil, MS 286 CH.sub.3 3-pyrazolylcarbonyl Et Br,
H iC.sub.3 H.sub.7 171-173 287 CH.sub.3 4-methoxyphenylcarbonyl Et
Br, H iC.sub.3 H.sub.7 104-106 288 CH.sub.3 2-furylcarbonyl Et Br,
H iC.sub.3 H.sub.7 136-138 289 CH.sub.3
bis(4-methoxyphenyl)hydroxymethyl Et Br, H iC.sub.3 H.sub.7 63-65
290 CH.sub.3 bis(2-furyl)hydroxymethyl Et Br, H iC.sub.3 H.sub.7
97-99 291 CH.sub.3 (2-furyl)hydroxymethyl Et Br, H iC.sub.3 H.sub.7
oil, MS 292 CH.sub.3 (4-methoxyphenyl)hydroxymethyl Et Br, H
iC.sub.3 H.sub.7 oil, MS 293 CH.sub.3 diphenylhydroxymethyl Et Br,
H iC.sub.3 H.sub.7 56-58 294 CH.sub.3 bis(4-pyridyl)hydroxymethyl
Et Br, H iC.sub.3 H.sub.7 68-70 295 CH.sub.3
(1-hydroxy-1-methyl)ethyl Et Br, H iC.sub.3 H.sub.7 oil, MS 296
CH.sub.3 1-hydroxyethyl Et Br, H iC.sub.3 H.sub.7 oil, MS
*Hydrochloride salt
TABLE 2 ##STR56## Ex. R.sup.1 R.sup.3 R.sup.4 X, X' R.sup.5 mp,
.degree. C. 75 CH.sub.3 CH.sub.3 CH.sub.3 Br, H CH.sub.3 76
CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 O, H CH.sub.3 O 77 CH.sub.3
CH.sub.3 allyl Br, H H 78* CH.sub.3 CH.sub.3 CH.sub.3 Br, H
iC.sub.3 H.sub.7 178-179 79 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
H 80 CH.sub.3 morpholino CH.sub.3 Br, H CH.sub.3 81 CH.sub.3
CH.sub.3 CH.sub.2 H.sub.5 CH.sub.3 O, H CH.sub.3 O 82 CH.sub.3
CH.sub.3 CH.sub.3 Br, H Br 83 CH.sub.3 CH.sub.3 CH.sub.3 Br, H
CH.sub.2 H.sub.5 84 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
tC.sub.4 H.sub.9 85 CH.sub.3 CH.sub.3 CH.sub.3 Br, H tC.sub.4
H.sub.9 86 CH.sub.3 CH.sub.3 CH.sub.3 Br, H CF.sub.3 87 CH.sub.3
CH.sub.3 CH.sub.2 H.sub.5 Br, H CF.sub.3 88 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 O, CH.sub.3 O CH.sub.3 O 89 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 CH.sub.3 O, CH.sub.3 O CH.sub.3 O 90 CH.sub.3
morpholino C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 91 CH.sub.3
morpholino allyl Br, H iC.sub.3 H.sub.7 92 CH.sub.3 CH.sub.3 allyl
Br, H nC.sub.4 H.sub.9 93 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
nC.sub.4 H.sub.9 94 CH.sub.3 CH.sub.3 nC.sub.3 H.sub.7 Br, H
nC.sub.4 H.sub.9 95* CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 194-196 96 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
cC.sub.6 H.sub.11 97 C.sub.2 H.sub.5 C.sub.2 H.sub.5 C.sub.2
H.sub.5 Br, H iC.sub.3 H.sub.7 98 C.sub.2 H.sub.5 C.sub.2 H.sub.5
C.sub.2 H.sub.5 Br, H nC.sub.4 H.sub.9 99 CH.sub.3 4-CHO-piperazino
C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 100 CH.sub.3 CH.sub.3 allyl
Br, H iC.sub.3 H.sub.7 101 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H
iC.sub.3 H.sub.7 102 CH.sub.3 CF.sub.3 C.sub.2 H.sub.5 Br, H
iC.sub.3 H.sub.7 103 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, H
C.sub.2 H.sub.4 --OCH.sub.3 104 CH.sub.3 morpholino C.sub.2 H.sub.5
I, H iC.sub.3 H.sub.7 105 CH.sub.3 2-thiopheno C.sub.2 H.sub.5 Br,
H iC.sub.3 H.sub.7 106 CH.sub.3 CH.sub.3 CH.sub.2 CN Br, H iC.sub.3
H.sub.7 107 CH.sub.3 CH.sub.3 CH.sub.2 cyclopropyl Br, H iC.sub.3
H.sub.7 108 CH.sub.3 CH.sub.3 propargyl Br, H iC.sub.3 H.sub.7 109
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H C.sub.2 H.sub.4 --OCH.sub.3
110 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H CH.sub.2 --OCH.sub.3 111
CH.sub.3 morpholino C.sub.2 H.sub.5 I, H C.sub.2 H.sub.4
--OCH.sub.3 112 CH.sub.3 morpholino C.sub.2 H.sub.5 I, H CH.sub.2
--OCH.sub.3 113 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 S, H
CH.sub.2 --OCH.sub.3 114 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5
(CH.sub.3).sub.2 N, H CH.sub.2 --OCH.sub.3 115 CH.sub.3 CH.sub.3
C.sub.2 H.sub.5 CH.sub.3 S, H iC.sub.3 H.sub.7 116 CH.sub.3
CH.sub.3 C.sub.2 H.sub.5 (CH.sub.3).sub.2 N, H iC.sub.3 H.sub.7 117
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 S, H CH.sub.3 S 118
CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 S, H CH.sub.2
--SCH.sub.3 119 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 Br, Br iC.sub.3
H.sub.7 120 CH.sub.3 thiomorpholino C.sub.2 H.sub.5 Br, Br iC.sub.3
H.sub.7 121 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 I, H I 122 CH.sub.3
morpholino C.sub.2 H.sub.5 I, H I 123 H CH.sub.3 C.sub.2 H.sub.5
Br, H iC.sub.3 H.sub.7 124 CH.sub.3 N(CH.sub.3)CH.sub.2 --CH.sub.2
OH C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 125 CH.sub.3 CH.sub.3
CH.sub.2 CH.sub.3 CH.sub.3 O, CH.sub.3 O CH.sub.3 126 CH.sub.3
CH.sub.3 CH.sub.3 H, H I 127 CH.sub.3 CH.sub.3 CH.sub.3 I, H H 128
CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3, H H 129* H H CH.sub.2 CH.sub.3
Br, H iC.sub.3 H.sub.7 *Hydrochloride salt
TABLE 3 ##STR57## Ex. R.sup.1 R.sup.3 R.sup.4 X, X' R.sup.5 mp,
.degree. C. 130* CH.sub.3 O CH.sub.3 O CH.sub.2 CH.sub.3 Br, H
iC.sub.3 H.sub.7 104-106 *Hydrochloride salt
TABLE 4 ##STR58## Ex. R.sup.1 R.sup.3 R.sup.4 X, X' R.sup.5 mp,
.degree. C. 131* CH.sub.3 CH.sub.3 H Br, H iC.sub.3 H.sub.7 124-125
*Hydrochloride salt
TABLE 4 ##STR59## Ex. R.sup.1 R.sup.3 R.sup.4 X, X' R.sup.5 mp,
.degree. C. 131* CH.sub.3 CH.sub.3 H Br, H iC.sub.3 H.sub.7 124-125
*Hydrochloride salt
TABLE 6 ##STR60## Synth. Ex. Ex. R.sup.1 R.sup.3 R.sup.4 X, X'
R.sup.5 mp, .degree. C. 133 CH.sub.3 CH.sub.3 Et Br, H iC.sub.3
H.sub.7 oil, MS 134 23 CH.sub.3 morpholino Et Br, H iC.sub.3
H.sub.7 oil, MS 134* CH.sub.3 morpholino Et Br, H iC.sub.3 H.sub.7
59-63 135 CH.sub.3 thiomorpholino Et I, H iC.sub.3 H.sub.7 oil, MS
136 CH.sub.3 morpholino Et I, H iC.sub.3 H.sub.7 oil, MS 137
CH.sub.3 piperidinyl Et I, H iC.sub.3 H.sub.7 oil, MS 232 CH.sub.3
N'N-diethyl Et Br, H iC.sub.3 H.sub.7 oil, MS 233 Cl Cl Et Br, H
iC.sub.3 H.sub.7 oil, MS 234 OCH.sub.3 OCH.sub.3 Et Br, H iC.sub.3
H.sub.7 oil, MS 235 Cl Cl Et I, H iC.sub.3 H.sub.7 oil, MS 236
CH.sub.3 imidazolino Et Br, H iC.sub.3 H.sub.7 >200 237 CH.sub.3
morpholino Et Br, CH.sub.3 O CH.sub.3 O 90-95 238 CH.sub.3
N(CH.sub.3).sub.2 Et Br, CH.sub.3 O CH.sub.3 O 65-58 239 CH.sub.3
morpholino Et CH.sub.3 O, CH.sub.3 O CH.sub.3 O oil, MS 240
CH.sub.3 N(CH.sub.3).sub.2 Et Br, H iC.sub.3 H.sub.7 72-75 241
CH.sub.3 thiazolidino Et Br, H iC.sub.3 H.sub.7 70-72 242* 29
CH.sub.3 benzyloxy Et Br, H iC.sub.3 H.sub.7 89-90 243 CH.sub.3
phenyloxy Et Br, H iC.sub.3 H.sub.7 140-142 244 CH.sub.3
4-ethylcarboxypiperizine Et Br, CH.sub.3 O CH.sub.3 O 65-70 245
CH.sub.3 4-carboxypiperizine Et Br, CH.sub.3 O CH.sub.3 O 95-100
246 CH.sub.3 HC(CO.sub.2 Et).sub.2 Et Br, H iC.sub.3 H.sub.7 oil,
MS 247 CH.sub.3 PhCHCN Et Br, CH.sub.3 O CH.sub.3 O 50-52 248
CH.sub.3 morpholino iC.sub.3 H.sub.7 O Br, CH.sub.3, O CH.sub.3 O
oil, MS 249* 30 Cl Cl Et I, H CH(CH.sub.3).sub.2 OH oil, MS 250
CH.sub.3 Cl C.sub.2 H.sub.5 Br, H iC.sub.3 H.sub.7 oil, MS
*Hydrochloride salt
TABLE 7 ##STR61## Synth. X', Ex. Ex. R.sup.1 R.sup.2 R.sup.4 X
R.sup.5 R.sup.6 mp, .degree. C. 251 62 CH.sub.3 CH.sub.3 Et Br, OMe
Br 133-138 OMe 252 CH.sub.3 CH.sub.3 H H, OMe Br 179-181 OMe 253 61
CH.sub.3 CH.sub.3 Et H, OMe Br 143-145 OMe
TABLE 8 ##STR62## Synth. Ex. Ex. R.sup.1 R.sup.3 R.sup.30 X X'
R.sup.5 mp, .degree. C. 254 64 CH.sub.3 CH.sub.3 CN Br H i-Pr 105.8
313 CH.sub.3 CH.sub.3 CN I H i-Pr 314 CH.sub.3 CH.sub.3 CN Br
6-CH.sub.3 i-Pr 315 CH.sub.3 --morpholino CN I 6-CH.sub.3 i-Pr 316
CH.sub.3 Cl CN I H 1-methoxy ethyl 317 CH.sub.3 Ph CN I H 1-methoxy
ethyl 318 CH.sub.3 CH.sub.3 CN Cl H 1-methoxy ethyl 319 CH.sub.3
CH.sub.3 CN I H 1-methoxy ethyl 320 CH.sub.3 CH.sub.3 CN Br H
1-methoxy ethyl 321 CH.sub.3 --morpholino CN I CH.sub.3 OCH.sub.3
255 74 CH.sub.3 Cl CN Br H i-Pr 179.2 256 66 CH.sub.3 Ph CN Br H
i-Pr oil 322 CH.sub.3 Ph CN --SCH.sub.3 H i-Pr 323 CH.sub.3
CH.sub.3 H Cl OCH.sub.3 i-Pr 257 65 CH.sub.3 CH.sub.3 H Br H i-Pr
MS 343.08 324 CH.sub.3 CH.sub.3 H --SCH.sub.3 H i-Pr 258 68
CH.sub.3 CH.sub.3 CN Br OCH.sub.3 OCH.sub.3 MS 388.0 325 CH.sub.3
--morpholino H I 6-OCH.sub.3 i-Pr 259 75 CH.sub.3 Cl H Br H i-Pr MS
363.0 326 CH.sub.3 Ph H I H 1-methoxy ethyl 260 69 CH.sub.3
CH.sub.3 H Br OCH.sub.3 OCH.sub.3 MS 360.9 327 CH.sub.3 CH.sub.3 H
I H 1-methoxy ethyl 328 CH.sub.3 CH.sub.3 H Br H 1-methoxy ethyl
329 CH.sub.3 --morpholino H I 6-CH.sub.3 OCH.sub.3 330 CH.sub.3 Cl
H I 6-CH.sub.3 i-Pr 261 67 CH.sub.3 Ph H Br H i-Pr MS 405.1 331
CH.sub.3 --NHEt H Br H i-Pr 332 CH.sub.3 --NHC(.dbd.O)CH.sub.3 H Br
H i-Pr 333 CH.sub.3 OCH.sub.3 H Br H i-Pr 334 CH.sub.3 --OCH.sub.2
Ph H Br H i-Pr 335 CH.sub.3 CH.sub.2 OPh H Br H i-Pr 336 CH.sub.3
2-thiophenylmethoxy H Br H i-Pr 337 CH.sub.3 --OCH(OH)Ph H Br H
i-Pr 338 CH.sub.3 --n-propoxy H Br H i-Pr 339 CH.sub.3
--C(.dbd.O)N(Me).sub.2 H Br H i-Pr 340 CH.sub.3 --NHCH.sub.2 Ph H
Br H i-Pr 262 70 Cl CH.sub.3 CN Br H i-Pr 123.8 341 N--Me.sub.2
CH.sub.3 H Br H i-Pr 342 CH.sub.3 --CH.sub.2 OCH.sub.3 H Br H i-Pr
263 71 Cl CH.sub.3 H Br H i-Pr MS 363.0 343 CH.sub.3 CH.sub.3 Et Br
H i-Pr 344 CH.sub.3 CH.sub.3 --CCH Br H i-Pr
TABLE 9 ##STR63## Ex. R.sup.1 R.sup.3 X X' R.sup.5 345 CH.sub.3
CH.sub.3 Br H i-Pr 346 CH.sub.3 CH.sub.3 I H i-Pr 347 CH.sub.3
CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 348 CH.sub.3 --morpholino I
6-CH.sub.3 i-Pr 349 CH.sub.3 Ph Br H i-Pr 350 CH.sub.3 CH.sub.3 SMe
H i-Pr
TABLE 10 ##STR64## Ex. R.sup.1 R.sup.3 R.sup.30 X X' R.sup.5 351
CH.sub.3 CH.sub.3 H Br H i-Pr 352 CH.sub.3 CH.sub.3 H I H i-Pr 353
CH.sub.3 --morpholino CN Br H i-Pr 354 CH.sub.3 Ph CN Br H i-Pr 355
CH.sub.3 CH.sub.3 H SMe H i-Pr
TABLE 11 ##STR65## Synth. ms Ex. Ex. R.sup.5 R.sup.4 R.sup.3 X Z K
L (m + H) 264* CH.sub.3 ethyl CH.sub.3 Br CH CH CH 321 265*
OCH.sub.3 ethyl CH.sub.3 Br CH CH N 337 266* OCH.sub.3 ethyl
CH.sub.3 H CH CH N 259 267* OCH.sub.3 ethyl CH.sub.3 Br N CH N 409
356 i-Pr ethyl CH.sub.3 Br N N N 357 i-Pr allyl CH.sub.3 Br N N N
358 i-Pr allyl CH.sub.3 Br CH N N 359 i-Pr ethyl CH.sub.3 Br CH N N
360 i-Pr ethyl morpholino Br N N N 361 i-Pr allyl morpholino Br N N
N 362 i-Pr allyl morpholino Br CH N N 363 i-Pr ethyl morphoiino Br
CH N N 364 OCH.sub.3 ethyl CH.sub.3 Br N N N 365 OCH.sub.3 allyl
CH.sub.3 Br N N N 366 OCH.sub.3 allyl CH.sub.3 Br CH N N 367
OCH.sub.3 ethyl CH.sub.3 Br CH N N 368 OCH.sub.3 ethyl morpholino
Br N N N 369 OCH.sub.3 allyl morpholino Br N N N 370 OCH.sub.3
allyl morpholino Br CH N N 371 OCH.sub.3 ethyl morpholino Br CH N N
372 OCH.sub.3 ethyl CH.sub.3 OCH.sub.3 N N N 373 OCH.sub.3 allyl
CH.sub.3 OCH.sub.3 N N N 374 105 OCH.sub.3 allyl CH.sub.3 OCH.sub.3
CH N N 290 375 OCH.sub.3 ethyl CH.sub.3 OCH.sub.3 CH N N 376
OCH.sub.3 ethyl morpholino OCH.sub.3 N N N 377 OCH.sub.3 allyl
morpholino OCH.sub.3 N N N 378 OCH.sub.3 allyl morpholino OCH.sub.3
CH N N 379 OCH.sub.3 ethyl morpholino OCH.sub.3 CH N N 380
OCH.sub.3 ethyl OCH.sub.3 OCH.sub.3 N N N 381 OCH.sub.3 allyl
OCH.sub.3 OCH.sub.3 N N N 382 OCH.sub.3 allyl OCH.sub.3 OCH.sub.3
CH N N 383 OCH.sub.3 ethyl OCH.sub.3 OCH.sub.3 CH N N 384 OCH.sub.3
ethyl OCH.sub.2 CH.sub.3 OCH.sub.3 N N N 385 OCH.sub.3 allyl
OCH.sub.2 CH.sub.3 OCH.sub.3 N N N 386 OCH.sub.3 allyl OCH.sub.2
CH.sub.3 OCH.sub.3 CH N N 387 OCH.sub.3 ethyl OCH.sub.2 CH.sub.3
OCH.sub.3 CH N N *Hydrochloride salt
TABLE 12 ##STR66## Ex. R.sup.1 R.sup.3 R.sup.30 X X' R.sup.5 388
CH.sub.3 CH.sub.3 CN Br H i-Pr 389 CH.sub.3 CH.sub.3 CN I H i-Pr
390 CH.sub.3 CH.sub.3 CN Br 6-CH.sub.3 i-Pr 391 CH.sub.3
-morpholino CN I 6-CH.sub.3 i-Pr 392 CH.sub.3 Cl CN I H 1-methoxy
ethyl 393 CH.sub.3 Ph CN I H 1-methoxy ethyl 394 CH.sub.3 CH.sub.3
CN Cl H 1-methoxy ethyl 395 CH.sub.3 CH.sub.3 CN I H 1-methoxy
ethyl 396 CH.sub.3 CH.sub.3 CN Br H 1-methoxy ethyl 397 CH.sub.3
-morpholino CN I CH.sub.3 OCH.sub.3 398 CH.sub.3 Cl CN Br H i-Pr
399 CH.sub.3 Ph CN Br H i-Pr 400 CH.sub.3 Ph CN --SCH.sub.3 H i-Pr
401 CH.sub.3 CH.sub.3 H Cl OCH.sub.3 i-Pr 402 CH.sub.3 CH.sub.3 H
Br H i-Pr 403 CH.sub.3 CH.sub.3 H --SCH.sub.3 H i-Pr 404 CH.sub.3
CH.sub.3 CN Br OCH.sub.3 OCH.sub.3 405 CH.sub.3 -morpholino H I
6-OCH.sub.3 i-Pr 406 CH.sub.3 Cl H Br H i-Pr 407 CH.sub.3 Ph H I H
1-methoxy ethyl 408 CH.sub.3 CH.sub.3 H Br OCH.sub.3 OCH.sub.3 409
CH.sub.3 CH.sub.3 H I H 1-methoxy ethyl 410 CH.sub.3 CH.sub.3 H Br
H 1-methoxy ethyl 411 CH.sub.3 -morpholino H I 6-CH.sub.3 OCH.sub.3
412 CH.sub.3 Cl H I 6-CH.sub.3 i-Pr 413 CH.sub.3 Ph H Br H i-Pr 414
CH.sub.3 --NHEt H Br H i-Pr 415 CH.sub.3 --NHC(.dbd.O)CH.sub.3 H Br
H i-Pr 416 CH.sub.3 OCH.sub.3 H Br H i-Pr 417 CH.sub.3 --OCH.sub.2
Ph H Br H i-Pr 418 CH.sub.3 CH.sub.2 OPh H Br H i-Pr 419 CH.sub.3
2-thiophenyl methoxy H Br H i-Pr 420 CH.sub.3 OCH(OH)Ph H Br H i-Pr
421 CH.sub.3 --n-propoxy H Br H i-Pr 422 CH.sub.3 --C(.dbd.O)N(Me)
H Br H i-Pr 423 CH.sub.3 --NHCH.sub.2 Ph H Br H i-Pr 424 CH.sub.3
CH.sub.3 CN Br H i-Pr 425 N--Me.sub.2 CH.sub.3 H Br H i-Pr 426
CH.sub.3 --CH.sub.2 OCH.sub.3 H Br H i-Pr 427 Cl CH.sub.3 H Br H
i-Pr 428 CH.sub.3 CH.sub.3 Et Br H i-Pr 429 CH.sub.3 CH.sub.3 --CCH
Br H i-Pr
TABLE 13 ##STR67## Ex. R.sup.1 R.sup.3 R.sup.30 X X' R.sup.5 430
CH.sub.3 CH.sub.3 CN Br H i-Pr 431 CH.sub.3 CH.sub.3 CN I H i-Pr
432 CH.sub.3 CH.sub.3 CN Br 6-CH.sub.3 i-Pr 433 CH.sub.3
-morpholino CN I 6-CH.sub.3 i-Pr 434 CH.sub.3 Cl CN I H 1-methoxy
ethyl 435 CH.sub.3 Ph CN I H 1-methoxy ethyl 436 CH.sub.3 CH.sub.3
CN Cl H 1-methoxy ethyl 437 CH.sub.3 CH.sub.3 CN I H 1-methoxy
ethyl 438 CH.sub.3 CH.sub.3 CN Br H 1-methoxy ethyl 439 CH.sub.3
-morpholino CN I CH.sub.3 OCH.sub.3 440 CH.sub.3 Cl CN Br H i-Pr
441 CH.sub.3 Ph CN Br H i-Pr 442 CH.sub.3 Ph CN --SCH.sub.3 H i-Pr
443 CH.sub.3 CH.sub.3 H Cl OCH.sub.3 i-Pr 444 CH.sub.3 CH.sub.3 H
Br H i-Pr 445 CH.sub.3 CH.sub.3 H --SCH.sub.3 H i-Pr 446 CH.sub.3
CH.sub.3 CN Br OCH.sub.3 OCH.sub.3 447 CH.sub.3 -morpholino H I
6-OCH.sub.3 i-Pr 448 CH.sub.3 Cl H Br H i-Pr 449 CH.sub.3 Ph H I H
1-methoxy ethyl 450 CH.sub.3 CH.sub.3 H Br OCH.sub.3 OCH.sub.3 451
CH.sub.3 CH.sub.3 H I H 1-methoxy ethyl 452 CH.sub.3 CH.sub.3 H Br
H 1-methoxy ethyl 453 CH.sub.3 -morpholino H I 6-CH.sub.3 OCH.sub.3
454 CH.sub.3 Cl H I 6-CH.sub.3 i-Pr 455 CH.sub.3 Ph H Br H i-Pr 456
CH.sub.3 --NHEt H Br H i-Pr 457 CH.sub.3 --NHC(.dbd.O)CH.sub.3 H Br
H i-Pr 458 CH.sub.3 OCH.sub.3 H Br H i-Pr 459 CH.sub.3 --OCH.sub.2
Ph H Br H i-Pr 460 CH.sub.3 CH.sub.2 OPh H Br H i-Pr 461 CH.sub.3
2-thiophenyl methoxy H Br H i-Pr 462 CH.sub.3 OCH(OH)Ph H Br H i-Pr
463 CH.sub.3 --n-propoxy H Br H i-Pr 464 CH.sub.3
--C(.dbd.O)N(Me).sub.2 H Br H i-Pr 465 CH.sub.3 --NHCH.sub.2 Ph H
Br H i-Pr 466 Cl CH.sub.3 CN Br H i-Pr 467 N--Me.sub.2 CH.sub.3 H
Br H i-Pr 468 CH.sub.3 --CH.sub.2 OCH.sub.3 H Br H i-Pr 469 Cl
CH.sub.3 H Br H i-Pr 470 CH.sub.3 CH.sub.3 Et Br H i-Pr 471
CH.sub.3 CH.sub.3 --CCH Br H i-Pr
TABLE 14 ##STR68## Ex. R.sup.1 R.sup.3 R.sup.30 X X' R.sup.5 472
CH.sub.3 CH.sub.3 CN Br H i-Pr 473 CH.sub.3 CH.sub.3 CN I H i-Pr
474 CH.sub.3 CH.sub.3 CN Br 6-CH.sub.3 i-Pr 475 CH.sub.3
-morpholino CN I 6-CH.sub.3 i-Pr 476 CH.sub.3 Cl CN I H 1-methoxy
ethyl 477 CH.sub.3 Ph CN I H 1-methoxy ethyl 478 CH.sub.3 CH.sub.3
CN Cl H 1-methoxy ethyl 479 CH.sub.3 CH.sub.3 CN I H 1-methoxy
ethyl 480 CH.sub.3 CH.sub.3 CN Br H 1-methoxy ethyl 481 CH.sub.3
-morpholino CN I CH.sub.3 OCH.sub.3 482 CH.sub.3 Cl CN Br H i-Pr
483 CH.sub.3 Ph CN Br H i-Pr 484 CH.sub.3 Ph CN --SCH.sub.3 H i-Pr
485 CH.sub.3 CH.sub.3 H Cl OCH.sub.3 i-Pr 486 CH.sub.3 CH.sub.3 H
Br H i-Pr 487 CH.sub.3 CH.sub.3 H --SCH.sub.3 H i-Pr 488 CH.sub.3
CH.sub.3 CN Br OCH.sub.3 OCH.sub.3 489 CH.sub.3 -morpholino H I
6-OCH.sub.3 i-Pr 490 CH.sub.3 Cl H Br H i-Pr 491 CH.sub.3 Ph H I H
1-methoxy ethyl 492 CH.sub.3 CH.sub.3 H Br OCH.sub.3 OCH.sub.3 493
CH.sub.3 CH.sub.3 H I H 1-methoxy ethyl 494 CH.sub.3 CH.sub.3 H Br
H 1-methoxy ethyl 495 CH.sub.3 -morpholino H I 6-CH.sub.3 OCH.sub.3
496 CH.sub.3 Cl H I 6-CH.sub.3 i-Pr 497 CH.sub.3 Ph H Br H i-Pr 498
CH.sub.3 --NHEt H Br H i-Pr 499 CH.sub.3 --NHC(.dbd.O)CH.sub.3 H Br
H i-Pr 500 CH.sub.3 OCH.sub.3 H Br H i-Pr 501 CH.sub.3 --OCH.sub.2
Ph H Br H i-Pr 502 CH.sub.3 CH.sub.2 OPh H Br H i-Pr 503 CH.sub.3
2-thiophenyl methoxy H Br H i-Pr 504 CH.sub.3 OCH(OH)Ph H Br H i-Pr
505 CH.sub.3 -n-propoxy H Br H i-Pr 506 CH.sub.3
C(.dbd.O)N(Me).sub.2 H Br H i-Pr 507 CH.sub.3 --NHCH.sub.2 Ph H Br
H i-Pr 508 Cl CH.sub.3 CN Br H i-Pr 509 N--Me.sub.2 CH.sub.3 H Br H
i-Pr 510 CH.sub.3 --CH.sub.2 OCH.sub.3 H Br H i-Pr 511 Cl CH.sub.3
H Br H i-Pr 512 CH.sub.3 CH.sub.3 Et Br H i-Pr 513 CH.sub.3
CH.sub.3 --CCH Br H i-Pr
TABLE 15 ##STR69## Synth. Ex. Ex. R.sup.1 R.sup.3 X X' R.sup.5 Mp
(.degree. C.) 514 CH.sub.3 CH.sub.3 Br H i-Pr 515 CH.sub.3 CH.sub.3
I H i-Pr 516 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 517
CH.sub.3 -morpholino I 6-CH.sub.3 i-Pr 518 CH.sub.3 Ph Br H i-Pr
519 CH.sub.3 CH.sub.3 SMe H i-Pr 520 101 CH.sub.3 Cl Br H i-Pr
49-52 521 CH.sub.3 CH.sub.3 Br H i-Pr 522 CH.sub.3 CH.sub.3 I H
i-Pr 523 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 524 CH.sub.3
-morpholino I 6-CH.sub.3 i-Pr 525 CH.sub.3 Ph Br H i-Pr 526
CH.sub.3 CH.sub.3 SMe H i-Pr 527 102 CH.sub.3 -morpholino Br H i-Pr
132-135 528 CH.sub.2 CH.sub.3 CH.sub.3 Br H i-Pr 529 CH.sub.2
CH.sub.3 CH.sub.3 I H i-Pr 530 CH.sub.2 CH.sub.3 CH.sub.3 Br
6-OCH.sub.3 OCH.sub.3 531 CH.sub.2 CH.sub.3 -morpholino I
6-CH.sub.3 i-Pr 532 CH.sub.2 CH.sub.3 Ph Br H i-Pr 533 CH.sub.2
CH.sub.3 CH.sub.3 SMe H i-Pr 534 CH.sub.2 CH.sub.3 Cl Br H i-Pr 535
CH.sub.2 CH.sub.3 CH Br H i-Pr 536 CH.sub.2 CH.sub.3 CH.sub.3 I H
i-Pr 537 CH.sub.2 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 538
CH.sub.2 CH.sub.3 -morpholino I 6-CH.sub.3 i-Pr 539 CH.sub.2
CH.sub.3 Ph Br H i-Pr 540 CH.sub.2 CH.sub.3 CH.sub.3 SMe H i-Pr 541
CH.sub.2 CH.sub.3 -morpholino Br H i-Pr
TABLE 16 ##STR70## Synth. Ex. Ex. R.sup.1 R.sup.3 X X' R.sup.5 Mp
(.degree. C.) 542 CH.sub.3 CH.sub.3 Br H i-Pr 543 CH.sub.3 CH.sub.3
I H i-Pr 544 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 545
CH.sub.3 -morpholino I 6-CH.sub.3 i-Pr 546 CH.sub.3 Ph Br H i-Pr
547 CH.sub.3 CH.sub.3 SMe H i-Pr 548 103 CH.sub.3 Cl Br H i-Pr MS
368 549 CH.sub.3 CH.sub.3 Br H i-Pr 550 CH.sub.3 CH.sub.3 I H i-Pr
551 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3 552 CH.sub.3
-morpholino I 6-CH.sub.3 i-Pr 553 CH.sub.3 Ph Br H i-Pr 554
CH.sub.3 CH.sub.3 SMe H i-Pr 555 104 CH.sub.3 -morpholino Br H i-Pr
145-148 556 CH.sub.2 CH.sub.3 CH.sub.3 Br H i-Pr 557 CH.sub.2
CH.sub.3 CH.sub.3 I H i-Pr 558 CH.sub.2 CH.sub.3 CH.sub.3 Br
6-OCH.sub.3 OCH.sub.3 559 CH.sub.2 CH.sub.3 -morpholino I
6-CH.sub.3 i-Pr 560 CH.sub.2 CH.sub.3 Ph Br H i-Pr 561 CH.sub.2
CH.sub.3 CH.sub.3 SMe H i-Pr 562 CH.sub.2 CH.sub.3 Cl Br H i-Pr 563
CH.sub.2 CH.sub.3 CH.sub.3 Br H i-Pr 564 CH.sub.2 CH.sub.3 CH.sub.3
I H i-Pr 565 CH.sub.2 CH.sub.3 CH.sub.3 Br 6-OCH.sub.3 OCH.sub.3
566 CH.sub.2 CH.sub.3 -morpholino I 6-CH.sub.3 i-Pr 567 CH.sub.2
CH.sub.3 Ph Br H i-Pr 568 CH.sub.2 CH.sub.3 CH.sub.3 SMe H i-Pr 569
CH.sub.2 CH.sub.3 -morpholino Br H i-Pr
Utility
In vitro Receptor Binding Assay
Tissue Preparation: Male Sprague Dawley rats (180-200 g) were
sacrificed by decapitation and the cortex was dissected on ice,
frozen whole in liquid nitrogen and stored at -70.degree. C. until
use. On the day of assay, frozen tissue was weighed and homogenized
in 20 volumes of ice cold buffer containing 50 mM Tris, 10 mM
MgCl.sub.2, 2 mM EGTA, pH 7.0 at 22.degree. C. using a Polytron
(Brinkmann Instruments, Westbury, N.Y.; setting 6) for 20 s. The
homogenate was centrifuged at 48,000.times. g for 10 min at
4.degree. C. The supernatant was discarded, and the pellet was
re-homogenized in the same volume of buffer and centrifuged at
48,000.times. g for 10 min at 4.degree. C. The resulting pellet was
resuspended in the above buffer to a final concentration of 20-40
mg original wet weight/mL and used in the assays described below.
Protein determinations were performed according to the method of
Lowry (Lowry et al., J. Biol. Chem. 193:265 (1951)) using bovine
serum albumin as a standard.
CRF Receptor Binding: Receptor binding assays were carried out
essentially as described by E. B. De Souza, J. Neurosci. 7:88
(1987).
Saturation Curve Analysis
In saturation studies, 100 .mu.l .sup.125 I-ovine CRF (50 pM-10 nM
final concentration), 100 .mu.l of assay buffer (with or without 1
mM r/hCRF final concentration, to define the non-specific binding)
and 100 .mu.l of membrane suspension (as described above) were
added in sequence to 1.5 mL polypropylene microfuge tubes for a
final volume of 300 .mu.l. All assays were carried out at
equilibrium for 2 h at 22.degree. C. as described by E. B. De
Souza, J. Neurosci. 7:88 (1987). The reaction was terminated by
centrifugation of the tubes in a Beckman microfuge for 5 min at
12,000.times. g. Aliquots of the supernatant were collected to
determine the "free" radioligand concentration. The remaining
supernatant was aspirated and the pellets washed gently with
ice-cold PBS plus 0.01% Triton X-100; centrifuged again and
monitored for bound radioactivity as described above. Data from
saturation curves were analyzed using the non-linear least-squares
curve-fitting program LIGAND (P. J. Munson and D. Rodbard, Anal.
Biochem. 107:220 (1980)). This program has the distinct advantage
of fitting the raw experimental data on an untransformed coordinate
system where errors are most likely to be normally distributed and
uncorrelated with the independent variable. LIGAND does not expect
the non-specific binding to be defined arbitrarily by the
investigator, rather it estimates the value as an independent
variable from the entire data set. The parameters for the affinity
constants (K.sub.D) and receptor densities (B.sub.max) are also
provided along with statistics on the general "fit" of the
estimated parameters to the raw data. This program also offers the
versatility of analyzing multiple curves simultaneously, thus
improving the reliability of the data analysis and hence the
validity of the final estimated parameters for any saturation
experiment.
Competition Curve Analysis
In competition studies, 100 .mu.l [.sup.125 I] ovine CRF ([.sup.125
I] CRF; final concentration 200-300 pM) was incubated along with
100 .mu.l buffer (in the presence of varying concentrations of
competing ligands, typically 1 pM to 10 mM) and 100 .mu.l of
membrane suspension as prepared above to give a total reaction
volume of 300 .mu.l. The reaction was initiated by the addition of
membrane homogenates, allowed to proceed to equilibrium for 2 h at
22.degree. C. and was terminated by centrifugation (12,000.times.
g) in a Beckman microfuge to separate the bound radioligand from
free radioligand. The resulting pellets were surface washed twice
by centrifugation with 1 mL of ice-cold phosphate buffered saline
and 0.01% Triton X-100; the supernatants discarded and the pellets
monitored for radioactivity at approximately 80% efficiency. The
level of non-specific binding was defined in the presence of 1 mM
unlabeled rat/humanCRF (r/hCRF). Data from competition curves were
analyzed by the program LIGAND. For each competition curve,
estimates of the affinity of the radiolabeled ligand for the CRF
receptor ([.sup.125 I]CRF) were obtained in independent saturation
experiments and these estimates were constrained during the
analysis of the apparent inhibitory constants (K.sub.i) for the
peptides tested. Routinely, the data were analyzed using a one- and
two-site model comparing the "goodness of fit" between the models
in order to accurately determine the K.sub.i. Statistical analyses
provided by LIGAND allowed the determination of whether a
single-site or multiple-site model should be used. For both
peptides (.alpha.-helical CRF.sub.9-41 and d-PheCRF.sub.12-41), as
well as for all compounds of this invention, data were fit
significantly to a single site model; a two-site model was either
not possible or did not significantly improve the fit of the
estimated parameters to the data.
The results of the in vitro testing of the compounds of the
invention are shown in Table 17. It was found, for a representative
number of compounds of the invention, that either form of the
compound, be it the free-base or the hydrochloride salt, produced
essentially the same inhibition value in the binding assay.
A compound is considered to be active if it has an K.sub.i value of
less than about 10000 nM for the inhibition of CRF. In Table 17;
the K.sub.i values were determined using the assay conditions
described above. The K.sub.i values are indicated as follows:
+++=<500 nM; ++=501-2000 nM; +=2001-10000 nM.
TABLE 17 Example Synth. Inhibition No. Ex. K.sub.i (nM) 1 1 ++ 2 ++
3 ++ 4 2 +++ 5 ++ 6 ++ 7 +++ 8 +++ 9 3 +++ 10 +++ 11 +++ 12 ++ 13
+++ 14 ++ 15 +++ 16 4 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 5 +++ 22
++ 23 +++ 24 ++ 25 +++ 26 +++ 27 +++ 28 +++ 29 6 +++ 30 7 +++ 31 8
+++ 32 +++ 33 9 +++ 34 10 +++ 37 +++ 49 12 + 50 13 +++ 51 ++ 52 +
53 + 54 + 55 +++ 56 14 +++ 57 15 +++ 58 16 +++ 59 17 +++ 60 ++ 61
18 +++ 62 ++ 63 19 + 64 20 + 65 21 + 66 + 68 + 69 + 70 + 71 + 72 +
73 22 +++ 74 +++ 78 + 95 ++ 130 ++ 131 + 132 + 133 ++ 134 23 +++
135 +++ 136 +++ 137 +++ 138 24 +++ 139 25 +++ 140 26 +++ 141 +++
142 +++ 143 +++ 145 + 146 + 147 +++ 148 +++ 149 +++ 150 +++ 151 +++
152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++ 159 27 +++
160 28 +++ 161 +++ 162 +++ 163 ++ 165 31 +++ 166 34 +++ 167 32 +++
168 35 +++ 170 36 +++ 171 38 +++ 172 39 +++ 173 40 ++ 174 41 +++
175 42 ++ 176 43 +++ 177 33 ++ 178 44 +++ 179 45 + 180 46 +++ 181
47 +++ 182 48 +++ 183 49 + 184 ++ 185 51 +++ 186 52 +++ 187 +++ 188
54 +++ 189 55 +++ 190 56 +++ 191 57 +++ 192 +++ 193 +++ 194 +++ 195
+++ 196 +++ 197 ++ 201 +++ 203 ++ 204 + 205 +++ 206 +++ 207 +++ 208
+++ 209 +++ 210 ++ 211 +++ 212 +++ 213 +++ 214 ++ 215 ++ 216 +++
217 +++ 218 +++ 219 +++ 221 +++ 222 58 ++ 223 ++ 224 63 +++ 225 59
+++ 226 +++ 227 +++ 228 ++ 229 + 230 60 +++ 231 + 232 +++ 236 +++
237 +++ 238 +++ 239 +++ 240 +++ 241 +++ 242 29 ++ 243 + 244 + 245 +
246 +++ 247 +++ 248 +++ 249 30 + 250 ++ 251 62 ++ 252 + 253 61 ++
254 64 +++ 255 74 ++ 256 66 +++ 257 65 +++ 258 68 +++ 259 75 +++
260 69 +++ 261 67 +++ 262 70 +++ 263 71 +++ 264 77 + 265 76 +++ 266
78 ++ 267 79 +++ 268 +++ 269 +++ 270 + 271 +++ 272 + 273 ++ 274 +
275 +++ 276 +++ 277 +++ 278 +++ 279 +++ 280 +++ 281 +++ 282 +++ 283
+ 284 +++ 285 +++ 286 +++ 287 ++ 288 +++ 289 +++ 290 +++ 291 +++
292 +++ 293 +++ 294 +++ 295 +++ 296 +++ 297 80 +++ 298 82 +++ 299
83 +++ 300 84 +++ 301 85 +++ 302 86 +++ 303 87 +++ 304 88 +++ 305
89 +++ 307 91 +++ 308 92 +++ 309 93 +++ 310 94 ++ 311 95 +++ 312 96
+++
Inhibition of CRF-Stimulated Adenylate Cyclase Activity
Inhibition of CRF-stimulated adenylate cyclase activity was
performed as described by G. Battaglia et al., Synapse 1:572
(1987). Briefly, assays were carried out at 37.degree. C. for 10
min in 200 mL of buffer containing 100 mM Tris-HCl (pH 7.4 at
37.degree. C.), 10 mM MgCl.sub.2, 0.4 mM EGTA, 0.1% BSA, 1 mM
isobutylmethylxanthine (IBMX), 250 units/mL phosphocreatine kinase,
5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM
oCRF, antagonist peptides (concentration range 10.sup.-9 to
10.sup.-6m) and 0.8 mg original wet weight tissue (approximately
40-60 mg protein). Reactions were initiated by the addition of 1 mM
ATP/.sup.32 P]ATP (approximately 2-4 mCi/tube) and terminated by
the addition of 100 mL of 50 mM Tris-HCl, 45 mM ATP and 2% sodium
dodecyl sulfate. In order to monitor the recovery of cAMP, 1 .mu.l
of [.sup.3 H]cAMP (approximately 40,000 dpm) was added to each tube
prior to separation. The separation of [.sup.32 P]cAMP from
[.sup.32 P]ATP was performed by sequential elution over Dowex and
alumina columns. Recovery was consistently greater than 80%.
Representative compounds of this invention were found to be active
in this assay. IC.sub.50 <10,000 nanomolar.
In Vivo Biological Assay
The in vivo activity of the compounds of the present invention can
be assessed using any one of the biological assays available and
accepted within the art. Illustrative of these tests include the
Acoustic Startle Assay, the Stair Climbing Test, and the Chronic
Administration Assay. These and other models useful for the testing
of compounds of the present invention have been outlined in C. W.
Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990).
Compounds may be tested in any species of rodent or small mammal.
Disclosure of the assays herein is not intended to limit the
enablement of the invention.
The foregoing tests results demonstrate that compounds of this
invention have utility in the treatment of imbalances associated
with abnormal levels of corticotropin releasing factor in patients
suffering from depression, affective disorders, and/or anxiety. The
foregoing tests also demonstrate that compounds of this invention
have utility in the treatment of uterine contraction disorders.
Compounds of this invention can be administered to treat said
abnormalities by means that produce contact of the active agent
with the agent's site of action in the body of a mammal. The
compounds can be administered by any conventional means available
for use in conjunction with pharmaceuticals either as individual
therapeutic agents or in a combination of therapeutic agents. They
can be administered alone, but are generally administered with a
pharmaceutical carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice.
The dosage administered will vary depending on the use and known
factors such as the pharmacodynamic character of the particular
agent, and its mode and route of administration; the recipient's
age, weight, and health; nature and extent of symptoms; kind of
concurrent treatment; frequency of treatment; and desired effect.
For use in the treatment of said diseases or conditions, the
compounds of this invention can be orally administered daily at a
dosage of the active ingredient of 0.002 to 200 mg/kg of body
weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one
to four times a day, or in sustained release formulation is
effective in obtaining the desired pharmacological effect.
Dosage forms (compositions) suitable for administration contain
from about 1 mg to about 100 mg of active ingredient per unit. In
these pharmaceutical compositions, the active ingredient will
ordinarily be present in an amount of about 0.5 to 95% by weight
based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage
forms, such as capsules, tablets and powders; or in liquid forms
such as elixirs, syrups, and/or suspensions. The compounds of this
invention can also be administered parenterally in sterile liquid
dose formulations.
Gelatin capsules can be used to contain the active ingredient and a
suitable carrier, such as, but not limited to, lactose, starch,
magnesium stearate, steric acid, or cellulose derivatives. Similar
diluents can be used to make compressed tablets. Both tablets and
capsules can be manufactured as sustained release products to
provide for continuous release of medication over a period of time.
Compressed tablets can be sugar-coated or film-coated to mask any
unpleasant taste, or used to protect the active ingredients from
the atmosphere, or to allow selective disintegration of the tablet
in the gastrointestinal tract.
Liquid dose forms for oral administration can contain coloring or
flavoring agents to increase patient acceptance.
In general, water, pharmaceutically acceptable oils, saline,
aqueous dextrose (glucose), and related sugar solutions and
glycols, such as propylene glycol or polyethylene glycol, are
suitable carriers for parenteral solutions. Solutions for
parenteral administration preferably contain a water soluble salt
of the active ingredient, suitable stabilizing agents, and if
necessary, buffer substances. Antioxidizing agents, such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either alone or in
combination, are suitable stabilizing agents. Also used are citric
acid and its salts, and EDTA. In addition, parenteral solutions can
contain preservatives such as benzalkonium chloride, methyl- or
propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in "Remington's
Pharmaceutical Sciences", A. Osol, a standard reference in the
field.
Useful pharmaceutical dosage-forms for administration of the
compounds of this invention can be illustrated as follows:
Capsules
A large number of units in the form of capsules are prepared by
filling standard two-piece hard gelatin capsules each with 100 mg
of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and
6 mg magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean,
cottonseed oil, or olive oil is prepared and injected by means of a
positive displacement into gelatin to form soft gelatin capsules
containing 100 mg of the active ingredient. The capsules are washed
and dried.
Tablets
A large number of tablets are prepared by conventional procedures
so that the dosage unit is 100 mg active ingredient, 0.2 mg of
colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of
microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose.
Appropriate coatings may be applied to increase palatability or
delayed adsorption.
The compounds of this invention may also be used as reagents or
standards in the biochemical study of neurological function,
dysfunction, and disease.
* * * * *